3 Antitussive Drugs

3

ANTITUSSIVE DRUGS C. I. CHAPPEL and C.

VON

SEEMANN

INTRODUCTION

THE present review attempts to report progress in antitussive therapy achieved over the past twenty years. I t is limited to those drugs which have a direct and specific action on the cough reflex, and includes the opium alkaloids, their synthetic derivatives and substitutes, and newer non-narcotic compounds. Such a classification eliminates adjuvant drugs such as expectorant~~ and - ~ antibiotics which are generally used in the treatment of cough accompanying respiratory disorders. A number of review articles on cough therapy and the management of cough have already been p~blished~-~O, and the problem of addiction to antitussive drugs has been ~ t r e s s e d ~ l - ~ ~ . Progress in this field has, however, been handicapped by the lack of simple and reliable methods for pharmacological testing34, although greater insight into the pathophysiology of cough and the nervous pathways involved in the cough reflex has enabled the pharmacologist in some cases to determine by specific techniques the site of action of antitussive drugs. PATHOPHYSIOLOGY OF COUGH

Description of Cough Cough may be defined as a series of phenomena of reflex or voluntary origin which combine to produce the rapid expulsion of air from the respiratory tract35. Preceding the expiratory thrust there is an inspiratory effort36, and the degree of pulmonary expansion with inspiration is directly related to the magnitude of the succeeding e ~ p i r a t i o n ~ ~As l ~ 'lung . expansion increases, so the inspiratory activity of the respiratory centre in the brain is more and more inhibited whilst increased stimulation of expiration develops. The link between inspiration and the subsequent expiration is probably through the Hering-Breuer reflex. When inspiration is complete, the glottis closes and remains closed as the expiratory phase begins. I t then suddenly opens and the high intratracheal pressure reinforces the expiratory effort. The action of the glottis in this respect is not obligatory as cough may occur in animals breathing through a tracheotomy tube-the glottis acts rather to facilitate and synchronize the cough. The bronchi and trachea may also help to increase the resistance of the respiratory tract to the expired air. Irritation and of the bronchi to produce cough also causes bronchoconstriction38~3g, X-ray studies have shown marked narrowing of the lumen of the trachea in man during co~gh40,~l. After inspiration and closure of the glottis, the expiratory phase of coughing begins. This is an active phenomenon involving contraction of the expiratory musculature of the thorax42. As the glottis is closed, a rapid and marked

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increase in intrapleural pressure extending over the lung parenchyma results43. This high intrathoracic pressure exists only until the glottis opens and expiration begins. The increased pressure within the lung combines with the resistance offered by the respiratory tract, and results in expulsion of air at enormous velocity. Recent calculations place the linear velocity of the air within the trachea during cough near to the speed of sound40. The events described are typical of a single cough, but cough is often repetitive, consisting of a series of such events. Whereas the Hering-Breuer reflex represents the connection between inspiration and the succeeding expiration in a single cough, indiviudal cough spasms may be linked through Head’s ‘paradoxical reflex,’ i.e. a strong expiration may lead to a stronger succeeding i n ~ p i r a t i o n ~Thus ~ . a vicious circle may be established whereby involuntary coughing becomes a paroxysm of uncontrolled coughs.

The cough reJzex As involuntary cough is a reflex action, it follows that there exists a reflex arc consisting of receptor or sensory areas, an afferent branch transmitting the sensation to the brain, a central regulating mechanism, and an efferent branch passing from the brain to the muscle involved. Experimental production of cough consists of provoking this reflex a t one or more points, while inhibition of cough is the result of a decrease in irritability or conduction a t one or more parts of the reflex arc. The sensory areas for cough are widely distributed in the mucous membrane of the upper respiratory tract. Dogs and rabbitsd5respond with strong coughs when the carina and division points ofthe main bronchi are stimulated. I n the at^^$^^, the larynx is the most sensitive area, with the lower half of the trachea only slightly less sensitive. Physiological differences in the character of the cough in the cat produced by stimulation of different areas46 may simulate the clinical cough in different disease states47~~s. There appear to be three main types of r e c e p t o r ~ ~ ~(-I~) lthe : subepithelial endings which respond to mechanical or chemical stimuli, (2) smooth muscle spindles which are activated by pulmonary inflation or deflation (the stretch receptors), and ( 3 )perichondrial receptors. The smooth muscle located in the large bronchi and trachea may be responsible for the HeringBreuer deflation reflex or the paradoxical reflex of Head38,52,whereas the rapidly adapting subepithelial endings are found most frequently in the lower half of the trachea and around the b i f ~ r c a t i o nAccording ~~. to ErnsP4, cough may be produced in cats with pleuritis by slight external pull on the trachea, and electrical stimulation of the visceral pleura of the dog has also been shown to cause coughing53. I n man, congestion of the pulmonary circulation as a result of increased resistance in the systemic c i r c u l a t i ~ n ~ ~ , tactile stimulation of the external auditory passages5, pressure on the liver and spleens6, compression of the carotid sinus, and chemical stimulation of the carotid bodies are additional stimuli effective in producing cough5’. The afferent branch of the cough reflex consists of: ( I ) the vagus nerve and its branches, with most of the vagal impulses originating in the stretch receptors of the lung5S, ( 2 ) the sensory innervation to the larynx which is supplied by the superior laryngeal nerve, ( 3 ) the glossopharyngeal n e r ~ e 4 4 , ~ ~ which transmits nerve impulses from the ear, and ( 4 ) some sympathetic

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nerve trunks60,61. The efferent branch of the cough reflex consists o f ( I ) the motor nerves to the striated respiratory musculature, (2) the efferent vagal fibres which innervate the smooth muscle of the trachea and bronchi, ( 3 ) the phrenic nerve which controls the diaphragm, and ( 4 ) the recurrent nerve which closes the glottis. The major gap in the knowledge of the physiology of cough lies in the central coordinating mechanism. A specific cough centre in the dorsolateral region of the medulla in the cat has been p o s t ~ l a t e d ~ However, ~,~~,~~ it .may be preferable to think of the central part of the reflex arc as a pathway involving the mechanisms which normally control respiration. Stimulation of the afferent part of the reflex pathway initiates the reflex whereas inhibition at any point by antitussive drugs depresses the remaining components of the reflex. The central reflex pathways may also be the site of coordination of the involuntary cough reflex with the higher centres. Nervous cough may be initiated by impulses from higher centres, while suppression of cough either voluntarily or through hypnosis may occur through such a mechanism'j3. PHARMACOLOGICAL APPROACH T O COUGH

Action on Sensory Zones

Nerve endings situated in the larynx and trachea may be blocked experimentally by painting the mucosa with local anaesthetic d r ~ g ~ ~ and ~ , ~ ~ , ~ ~ * these agents are used as sprays, e.g. in bronchoscopy to abolish the cough reflex3'j. Antitussives with a selective anaesthetic activity on the stretch receptors of the lung have been d e ~ e l o p e d and ~ ~ , several ~~ authors have traced this e f f e ~ t ~ ~Lobeline * ~ ~ - produces ~~. cough when given intravenously to man5', and this action may be suppressed by pretreatment with hexamethonium56. Hexamethonium also inhibits cough produced in man by inhalation of an aerosol of a c e t y l ~ h o l i n e ~ ~ ~ ~ ~ .

Action on Aferent Transmission The afferent transmission of nerve impulses from the lung in the cough reflex resides mainly in the v a g u P , and to a lesser extent in sympathetic fibres from the stellate ganglione0. Transection of the vagi abolishes cough produced by ~ h e m i c a l ~ or ~ ?mechanicalel ~O stimulation of the trachea of the cat and rabbit. In the dog exposed to ammonia vapourB0,and sometimes in cats after mechanical stimulation of the trachea61, thoracic sympathectomy may also be necessary to eliminate cough reflex completely. Unilateral vagotomy has been used in man as a surgical approach in intractable but more experimental work is needed in this line.

Action on Central Mechanisms Morphine, codeine and their derivatives act on central respiratory mechanisms, and codeine is generally accepted as the prototype of antitussives having a central point of attack. Other drugs believed to act on central pathways are general anaesthetic^^^, chloralosesl.7 4 and the barbiturate^'^. The central site remains the favourite target of the pharmacologist. 91

ANTITUSSIVE DRUGS

Action on Efferent Transmission I n theory, drugs which reduce neural transmission, such as the neuromuscular blocking agents, should be of value in the treatment of cough. However, in practical therapeutics several difficulties arise, the most important being respiratory paralysis. Papaverine suppresses cough induced by stimulation of the superior laryngeal nerve of the cat76but it is not known if this is related to its antispasmodic action. EVALUATION OF ANTITIJSSIVE DRUGS

Exfierimenla1 Animals The techniques that have been used are shown in Tables 3.1 and 3.2. Mayer ~ ~ Banister, Fegler and Hebb", and his c o - ~ o r k e r s 7 ~ as, well as L a r ~ e 1 1and Tab/e 3.1. Methods of producing experimental cough in animals by stimulation of the sensory zones

Anaesthetic used

None

Urethane Chloroform Chloralose __-Cat

None Chloralose Barbiturate

Guinea-pig

Rabbit Rat

None

Barbiturate ~ _ _ _ None

pte o f

References

stzmulatzon H,SO, aerosol NH, vapour Mechanical Electrical H,SO, aerosol NH, vapour Elcctrical Mechanical

91,96 93-95 82, 97, 98 100 113 92 53,99 115

Mechanical NH, vapour Mechanical NH, vapour Mechanical

34 60 81 64, 65, 65a 54,64, 65,65a, 114

Mechanical H,SO, acrosol NH, vapour SO, vapour Antigen aerosol Acrolein vapour

88 a3 84, 116 86-88 90 117

NH:, vapour _ SO, vapour

60

_________

~~

78, 79

found the rabbit to be the most sensitive animal for studies of a physiological nature on pulmonary reflexes. However, difficulties in maintaining rabbits in a uniform plane of anaesthesia and the tendency of these animals to sneeze rather than cough in response to chemical stimuli are reasons for their nonusage in routine antitussive testing. Difficulties in differentiating between coughs and sneezes have also been encountered in rats7sy79.The cat under normal physiological conditions seldom coughs but is satisfactory for antitussive studies when anaesthetized6", 6 4 , 6 6 , 6 5 a or d e ~ e r e b r a t e d 4 4 ~ ~I~t~is8 0the . animal of choice for the provocation of cough by electrical stimulation of the

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superior laryngeal nerve. Further, D ~ m e n j o zand ~ ~May and Widdicombesl were able to produce cough by this means in the cat but not in the dog. O n the other hand, KasCs2 succeeded in the dog by stimulating a branch of the main nerve. A number of authors have used the guinea-pig in antitussive testing, producing cough by exposing the animal to chemical irritant^^^-^^ or by mechanical irritation of the trachea88. This animal has the great advantage of being readily available as a laboratory test animal, although large Table 3 2 . Methods o f producing experimental cough in animals by electrical stimulation of afferent nerves or medulla

1

Species

I’og Cat

i

Guinea-pig

1

Anaesthetii

Nerve or medulla stimulated

None Barbiturate

Ckrvical vagus Superior laryngeal

75, 101 82, 85

Decerebrate Barbiturate

Medulla Medulla Superior laryngeal

62,80 42 65a, 74,76,85, 102, 103

Barbiturate

Superior laryngeal

85

Refereticts

numbers are often required to give reliable datasg. The guinea-pig has also been used for a study of cough during anaphylactic shockgo. The dog is perhaps the animal most widely used for antitussive screening. This species has been utilized without anaesthesia for the study of cough produced by c h e m i ~ a l ~ lor * ~mechanicals2~97~98 ~-~~ irritation of the respiratory mucosa. I n the anaesthetized dog, experimental cough has been produced by mechanical stimulation of the mucosa of the tracheas5, and electrical stimulation of the visceral pleura53, the tracheal mucosa99~100, and the cervical vagus75,82J01.These animals are much less variable in their cough response on repeated exposure to a chemical irritantg6,than are other species and thus may be reliably used in studying the duration of action of antitussi~es~l.

Anaesthesia Generally, anaesthetics depress the vegetative reflexes, which include the cough reflex. Nevertheless, satisfactory results have been obtained, provided a superficial plane of anaesthesia is maintained. Often the threshold of stimulation required to elicit cough is affected by a n a e s t h e ~ i a ~so~ ~ that *~~~, such animals cannot be used for studies of duration of drug action. Decerebration appears to have a great advantage over anaesthesia for acute studies623s0. Evaluation in Man The final stage in the development of a new antitussive drug is the clinical evaluation. The critical question is whether to use patients suffering from pathological cough or individuals with an experimentally induced cough. During the past 10 years or so, a number of authors have studied methods

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ANTITUSSIVE DRUGS

of eliciting cough by artificial means (see Table 3.3). Although mechanical stimuli have been employed118 most have used chemical s t i m u l i ~ ~ 4 ~ ~ ~ 2 ~ 1 ~ 9 ~ 1 2 0 , ammonia vapour being considered a reasonable agent. However, irritation of the nasal and laryngeal mucosa often resulted and later experiments have been carried out with a 10 per cent solution of citric acid in aerosol form; thk does not irritate the mucosa. The cough produced by the intravenous injection of lobeline was developed in 1950, but some workers found that it failed to respond to opium alkaloids although hexametlionium waS effective.

1

Tuble 7.3. Methods of producing esprrimmtal cough in man

Tyje of stimulation Mechanical Ammonia Lobeline Spray of ether or peppermint Acetylcholine aerosol Paralclehyde Citric acid aerosol

1

I

Yeat ~~~

1922 1950-52 1950-5 1

19.52 ..~-

1954 1954 1954-57

~

Kfiienre ~~

118 104-1 06 56, 111 119 71, 72, 120, 112 107 100, 109, 110

THERAPY OF C O U G H

The Opium Alkaloids Although there are r e p o r t ~ ~ of ~ lthe - ~use ~ ~of crude opium alkaloids in the treatment of cough, such preparations are now rarely used in medicine. I n the following sections only those classes of opium alkaloids which have attained importance as antitussives will be discussed, viz. morphine, codeine and their close derivatives, and noscapine. Morphine alkaloids and close derivatives The chemistry of the morphine alkaloids, which may be considered as being derived from the morphinan skeleton ( I ) , has been reviewed by H o l m e ~ l Holmes ~~, and Stork12Gand Stork127. Morphine-The alkaloid may be represented by formula (11,K = Me,

R1= R2= OH) and may be designated

as 3,6-dihydroxy-4,5-oxido-7,8-

dehydro- N-methylmorphinan. For therapeutic purposes the salts of the

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naturally occurring laevorotatory base, especially the hydrochloride and the sulphate, are usually employed. The pharmacology of morphine as an antitussive has been investigated thoroughly. E r n ~ was t ~ ~one of the early workers to find that morphine in doses of 0.5 mg/kg S.C. inhibited the cough reflex in cats, and in a subsequent paper12s he showed that codeine a t 3 mg/kg S.C. also inhibited this cough reflex. Eichler and Smiatek83, using a sulphuric acid aerosol to induce cough, later reported that doses of 1 mg/kg morphine S.C. reduced coughing in guinea-pigs. More recently, Friebel and Reichles7, using a similar method, classified morphine among the drugs with predominantly analgetic and less pronounced antitussive activity. They also confirmed this finding in another series of experiments using rats as test animals7s. The same authorslZyused morphine as the standard test substance in their comparison of the xelative analgetic and antitussive activities in laboratory animals with the activities found in clinical trials. Green and WardS5,using the experimental method of D0menjoz7~, besides methods involving cough induced by a sulphur dioxide aerosol, found the antitussive ED,, value for morphine sulphate to be 0.4 mg/kg i.v. They also reported that this action was inhibited by nalorphine, and that, of the drugs tested by them, morphine had the most marked depressing effect upon respiration. Rosiere, Winder and Waxg3later found that morphine sulphate was fourteen times more effective than codeine phosphate as an antitussive. Morphine (1 mg/kg i.m.) was also stated to inhibit experimental cough induced in dogs by faradic stimulation of the visceral pleura53. Morphine was inferior to methadone in preventing experimental cough induced by electrical stimulation of the tracheal mucosa of the anaesthetized cat130. Gross and Lebonl3I evaluated morphine by a method of experimental cough induced in the anaesthetized dog by means of faradic stimulation of the tracheal carina, and found that 0.5 mg/kg i.v. had no effect, whereas doubling this dose gave immediate cough suppression lasting for 20-30 minutes. Silvestrini and Maffii132found morphine to be a powerful antitussive in a number of different tests, especially in experiments using acrolein-induced cough in guinea-pigs, and classified it among the potent analgesics with antitussive activity. The antitussive ED,, of morphine hydrochloride in guinea-pigs exposed to sulphur dioxide aerosol has been reported to be 5.9 mg/kg s.c., and 6.4 mg/kg i.p. in the same animals after mechanical irritation of the tracheass. Its dextrorotatory enantiomer is less active than the laevorotatory form, the ED,, being reported as 10.4 mg/kg I n human subjects, morphine is a potent cough s u p p r e s ~ a n t l Yet, ~ ~ . in a double blind study, no significant differences in antitussive effects were found between morphine and placebo in experimental cough induced in a variety of ways in man107y134.Although the toxicity of morphine is low, its well-known depressant effect upon respiration may occasionally cause death. Wilson135has reported three fatalities in infants after administration of cough syrups containing morphine. Morphine-N-oxide (Genomorphine)-It has been reported to be considerably more potent than morphine in inhibiting experimental cough in guineap i g P , but it does not seem to have been accepted as an antitussive drug. compound was Dihydromorphine (III, R = Me, K1 = R2 = OH)-This

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ANTITUSSIVE DRUGS

found to be slightly more potent than morphine in inhibiting cough induced by sulphur dioxide in guinea-pigs, and considerably more potent in mechanically-induced c o ~ g h l ~ Its~ .dextrorotatory enantiomer has only about one-quarter of the antitussive activity of morphine133.

Dihydromorphine-N-oxide-I t is somewhat less potent than morphine136. Hydrornorphone (dihydrornorphinone, Dilaudid, III, R = Me, R1 = OH, R2 = ketonic oxygen)-This drug was classifieds7among those possessing both analgetic and antitussive properties. It has been reported to be clinically inferior to noscapine13', but to be very effective when administered rectally to infants and children in 1.25 mg doses138. Its dextrorotatory enantiomer has only about one-fifth of the antitussive activity of morphine133. Nalor-hine (N-al&orrnorphine, 11,R = CH2-CH=CH2, R1 = R2= OH)This compound inhibits the antitussive effects of morphinea5 and those of codeine and methadone130.Its close chemical relative, N-propylnormorphine (11,R = Pr, R1= R2= OH) inhibits codeines5. Nevertheless, some success followed treatment with 20 mg doses of nalorphine in clinical t r i a l ~ l ~ ~ J ~ ~ . Codeine and close derivatives Characterized by its chemical structure as morphine 3-methyl ether (II, R = Me, R1= OMe, R2= OH), codeine was regarded as the antitussive of choice for a considerable period of time. I t was recently estimated that almost one-third of the total codeine production of the United States was used for the preparation of cough mixtures. The pharmacology of codeine as an antitussive in animals was first investigated by E r n ~ t He ~ ~ found . that codeine inhibits the cough reflex in doses of 3 mg/kg s.c., and doses of 0.75 mg/kg S.C. are effective when given in association with 0.125 mg/kg morphine12s. Later, Green and Wards5 reported that the ED,, of codeine (as the free base) was 4 mg/kg i.v. when tested by Domenjoz's method'4. These authors found that its antitussive effect is abolished by n-propylnormorphine, and that cats rapidly become tolerant to its respiratory depressant effects. Codeine has been classified as one of the drugs with the highest antitussive and the lowest analgetic activities in guinea-pigss7 and in rats7a.Results obtained in rats and guineapigs compare reasonably well with those found in man129.Gross139reported that codeine a t 1-2 mg/kg p.0. inhibited experimental cough induced in dogs either by faradic stimulation of the visceral pleura or by lobeline. The antitussive activity of codeine and its inhibition by nalorphine was also 96

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investigated by Huet130. Silvestrini and M a f f ~ i found l ~ ~ codeine to be about as potent as morphine in inhibiting acrolein-induced cough in guinea-pigs, slightly less active in cats after mechanical irritation, and considerably less active than morphine when tested by the method of D o m e n j o ~ ? Codeine ~. (4 mg/kg i.v.) inhibits cough following electrical stimulation of the trachea in dogs, and its action becomes apparent only 30 minutes after administration and lasts for approximately 15 minutesl4O.Kohli, Gupta and Bhargava141 found that the antitussive ED,, of codeine, using the method of D o m e n j o ~ ' ~ , was 1.5 mg/kg i.v., a result in close agreement with that obtained by other a~thors75,132,'42,143. I n human subjects, H i l l i ~ found ~ ' ~ codeine as an antitussive to be no more effective than a placebo. I n a double-blind study using ammonia gas, citric acid aerosol or paraldehyde i.v. to produce cough, no significant differcnces were observed between the efficacy of codeine and that of p l a c e b ~ l ~ ' JBut ~~. Hoglund and Michaelsson104 found that 10, 15, 20, and 30 mg of codeine raised the threshold value of cough produced by ammonia gas for 30, 58, 95, and 100 minutes respectively. Trendelenburg'O'j, using a similar method, found 20 mg codeine to be about as effective as 2.2 mg methadone, but he reported that it inhibited respiration and that 40 mg codeine produced bradycardia and 'a feeling of tightness'. I n a double-blind evaluation of antitussives in healthy human subjects exposed to citric acid aerosol, codeine in 5, 10 and 20 mg doses was later found to be more effective than a placebo144.Doses of 15 mg codeine gave peak antitussive effects, during the first three hours after administration, equal to 2.5 mg methadone, with diminution of effects in the fourth howl4,. A carefully screened group of healthy volunteers who were exposed to critic acid aerosol144received protection with 30 mg doses of codeine146.Codeine was also found to be more effective than morphine or normethadone in inhibiting cough induced in man by paraldehyde i.v.lZ4. Clinical trials with doses of 10 and 25 mg of codeine in cases of pathologic cough showed a significant reduction in the frequency of coughlo'. I n a second the same authors observed five patients over a period of 45 days of treatment with 10 mg codeine given four times per day orally: no objective differences between codeine and placebo were found, although the patients reported codeine as being superior. The authors concluded from the results of their first studylo7that the sense of well-being imparted in the patients by codeine accounts for part of its purported antitussive efficacy. Codeine-N-oxide-In guinea-pigs this was found to be fourteen times more effective than codeine in inhibiting sulphur dioxide-induced cough, but only 1.6 times as effective in preventing cough following mechanical irritation136.The authors pointed out that it was a very weak analgesic and was less toxic than codeine, having less effect on blood pressure, respiration, heart rate, and intestinal peristalsis. Codeine Methobromide ( Tecodine)-The methobromide is an effective antitussive in dogs, about one-sixth as potent as methadone, but it possesses distinct respiratory depressant effects147. Bihydrocodeine (Paracodin, Hydrocodin, IlI, R = Me, R1 OMe, R2 = OH)-This compound was studied by Friebel and Reich1elz9, who found its antitussive effects in guinea-pigs to agree with results obtained in the clinic. I t 1

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ANTITUSSIVE DRUGS

has been reported to be about four times as active as codeine in guinea-pigs, even its dextrorotatory enantiomer having about 73 per cent of the antitussive activity of codeine136. Clinical studies with a dihydrocodeine aerosol treatment in cases of postoperative cough, pulmonary tuberculosis, pulmonary tuberculosis complicated by bronchitis, and cases complicated by bronchial asthma gave good results148. Patients who were refractory to the common antitussive preparations showed a good response when treated with a composition containing 5 mg dihydrocodeine and 25 mg n o ~ c a p i n e l ~ ~ . Dihydrocodeine-N-oxide-This possesses only very weak antitussive propertie~l~~. Hydrocodone-Well known for its narcotic properties, hydrocodone (Dihydrocodeinone, Dicodid, 111, R = Me, R1 = OMe, R2 = 0 (ketonic oxygen)) was first studied as an antitussive by E r n ~ twho ~ ~ found , it was more potent in the cat than codeine. Further pharmacological studies by Eichler and Smiateke3established that its antitussive activity in guinea-pigs is equal to that of morphine. I t has been classified among the drugs with intermediate analgetic and antitussive a c t i v i t i e ~ ~but ~ J Reichle ~~ and Friebel78 found it to have more pronounced antitussive than analgetic activities in the rat. I t is several times as active as, and with a longer duration of activity than, codeine in the d0g9139a,but slightly less active than morphine. Human pharmacology studies showed it to be more than twice as active as codeine, with no side-effects being notedlo6. I n a clinical trial Voiculescu and Neurnadso stated that hydrocodone was centrally active. I n recent years a preparation containing hydrocodone and phenyltoloxamine in the form of a resin complex (Tussionex) has been the subject of a number of clinical studies. Chan and Hays151 found this combination to be more effective in dogs than hydrocodone alone, and much more potent than either dihydrocodeine or codeine. They reported satisfactory results in patients with respiratory disorders when treated with the equivalent of 5 mg hydrocodone twice a day; duration of antitussive effect was six to twelve hours. I n a pharmacological study using normal subjects, Bickerman and Itkin145also found that the preparation gave sustained cough suppression over a period of seven hours. I t is effective in ~ h i l d r e n l ~but ~ J hydrocodone ~~ has habitforming propertiesls2. A double-blind clinical study carried out by Cass and F r e d e ~ - i kshowed l~~ that doses of ‘Tussionex’ containing 10 mg hydrocodone were more effective than doses of 5 mg, and both were superior to placebo controls. Dihydrocodeinone En01 Acetate (Acedicon, Thebacon, IT/)-This compound was reported by E r n ~ to t ~be~ as potent as morphine as an antitussive in cats. I n guinea-pigs, it ha? been variously described as having intermediate analgetic and antitussive activitiesa7, and also as being the most potent antitussive in guinea-pigs and in man129.H ~ s e n l in ~ ~a ,recent clinical study on patients with pulmonary tuberculosis and other pulmonary diseases, used 7.5-15 mg per day, and reported satisfactory to excellent results in nearly every case. Duration of antitussive effects was 6 to 10 hours, with an onset of action 10 to 30 minutes after ingestion. Treatment lasted from several weeks to six months, during which time no development of tolerance was noted, and no cases of addiction were encountered.

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Oxycodone (dihydrohydroxycodeinone, Eucodal, Eukodal, V )-This is among the drugs with intermediate analgetic and antitussive activities in guinea-pigss7.

MeCOO'

"

but in rats its action is mainly analgetic rather than a n t i t u s s i ~ eA ~ ~com. parison has been made between clinical results and those observed in mice, rats, and guinea-pigss7JZ9. Ethylmorphine (Dionin, morphine 3-ethyl ether, I[, R = Me, R1 = OEt, R2 = OH)-Classified among the compounds having closely associated analgetic and antitussive activities, it gave good agreement for antitussive data when tested in guinea-pig and mans7,lZ9. Pholcodine-Together with the corresponding dimethylaminoethyl, diethylaminoethyl, and piperidinoethyl ethers, pholcodine (3-(2-morpholinoethyl)

lZ9

morphine, 11, R = Me,

/-\

R1= 0 .CH, . CH,. N

0, R2 = O H ) , was

\-/

first prepared by Chabrier, Giudicelli and Thuillierll'. The title compound proved to have the most interesting properties. It has a low acute toxicity (LD,, 535 mg/kg i.p., 1010 mg/kg orally, mouse), a low subacute chronic toxicity (50 mg/kg mouse for 30 days tolerated by most animals) and weak activity upon the central nervous system. As an antitussive, pholcodine inhibited lobeline-induced cough in oral doses of 80-100 mg. Clinical reportslll indicated that it was effective in oral doses of 10-30 mg, with an onset of action 10-20 minutes after administration and a duration of effect of 1.5-4 hours, whilst daily intake of up to 120 mg caused no side-effects. A pharmacological study by May and Widdicombeal showed that it was three times as active as codeine and one half as potent as morphine in inhibiting expiratory effects due to mechanical irritation, but less active than either morphine or codeine in inhibiting inspiratory effects following inhalation of sulphur dioxide. Green and Warda5found that it was slightly more active than codeine in the cat, while P l i ~ n i e r lusing ~ ~ , the same technique, reported it to be twice as potent as codeine, with a similar degree of hypotension as codeine and marked bronchospastic properties, but less than one-half the toxicity of codeine. Snell and Arrnitagels7 reported that pholcodine was about as effective as heroin and significantly better than a placebo, in human subjects. Bickerman and I t k i r ~ later l ~ ~ found that it gave sustained cough suppression over a four-hour period, 10 mg being as effective as 15 mg codeine or 2.5 mg methadone. Pholcodine was also reported to be more active than

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morphine or normethadone in inhibiting cough induced in man by means of intravenous ~ a r a l d e h y d e l ~ Ryde158 ~. conducted a clinical trial on patients mainly suffering from pulmonary tuberculosis, and obtained good results with the Swedish combined preparation Tussukon, containing pholcodine and a polysorbate preparation. Diacetylmorphine (diamorphine, heroin, 11, R = Me, R1 = R2 = 0COMe)--It has apparently been investigated as a n antitussive only in human subjects. H i l l i ~ lin ~ ~an , experimental study on one volunteer, found it to be a potent cough suppressant, while other workers reported that it did not inhibit experimental The dangers of habituation or addiction inherent in the above group of drugs are well known and have recently been reviewed by Eddy, Halbach and B r a e n d e r ~ ~ It~should . be mentioned that Maller and C ~ n s t a n t i n e s c u ~ ~ have reported on five cases of true addiction to antitussive preparations containing codeine, ethylmorphine, and heroin.

Noscapine (Narcotine,Coscopine, Nicolane) Noscapine, an alkaloid present in crude opium to the extent of 3-10 per cent, was discovered by Robiquet in 1817. Its structure was established by Marshall, Pyman and Robinson159 as that of l-a-2-methyl-8-methoxy-6,7methylenedioxy- 1- (6,7-dimethoxy-3-phthalidyl) - 1,2,3,4-tetrahydroisoquinoline ( W).

oAo I I

Green and Wards5 were among the first to investigate its pharmacology. Reichle and Friet~el'~ thought it to be a potent, centrally active antitussive with little analgetic effects, and reported good agreement between data obtained for antitussive activities in rats, guinea-pigs, and man129. Van DongenlG0tested noscapine by the method of Ernst3* and reported it to be ineffective in inhibiting cough in doses of 1-5 mg/kg s.c., whilst higher doses caused undue excitation. The pharmacological results obtained up to the end of 1957 have been reviewed by ErveniusIG1. Silvestrini and Maffii132 found that noscapine was effective in inhibiting experimental cough elicited with ammonia or with acrolein aerosol in guinea-pigs or elicited after inhalation of sulphuric acid aerosol in dogs, but less effective after mechanical stimulation. La Barre and PIisniePz, who re-determined the antitussive ED,, of noscapine by a modification of Domenjoz's method7*, found that it was more effective than codeine, which was apt to produce bronchospasm, whereas noscapine increased the vital capacity and acted as 100

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a bronchodilator. Doses of 1 mg/kg noscapine orally have also, however, been reported to cause little inhibition of coughs1. In pharmacological experiments on human subjects, there are conflicting report~~ ono the ~ ~ effectiveness ~~~ of noscapine. Clinical evaluations of the compound as an antitussive showed that 5-15 mg doses gave a t most a 25 per cent reduction in the frequency of cough, but that patients evaluated it as better than a p l a ~ e b o l ~Voiculescu ~ J ~ ~ . and Neumanlso included it in a study of a number of antitussives, but failed to give details of their results, while another showed that divided daily doses of 15-60 mg were effective in the majority of the patients, with no serious side-effects such as gastrointestinal or respiratory complaints. Synthetic Compounds with Morphine-like Efects Pethidine (Meperidine, DemeroL, Dolantin, VII, ethyl l-methyl-4-phenylpiperidine4-carboxyLate)-This was the first of many synthetic compounds with morphine-like effects to he synthesized over the last twenty yearP3.

Its chemical and pharmacological properties were first discussed by Eisleb and Scha~rnann16~9 and it was investigated as an antitussive by Schaumannlss. Using the method of E r n ~ tit~was ~ , found to be active at 10 to 15 mg/kg s.c., hut about 5 times less potent than morphine. Green and Wards5 using the method of D ~ m e n j o zfound ~ ~ it to be less than half as active as morphine sulphate and about four times as active as codeine base. These authors also pointed out that, of all the drugs tested by them, this compound had the least depressant effect upon respiration. From a study of its analgetic and antitussive activities in guinea-pigs, it was shown that pethidine possesses mainly analgetic activity and little antitussive activity, while codeine was classified among the drugs with the highest antitussive activitya7. Buschkemlas, investigating pethidine as a cough-preventative during intratracheal anaesthesia, found that the drug was comparatively inactive during the first 30 minutes after administration, but gave a significant seduction in cough frequency during the second 30 minutes. Ketobemidone (Cliradon, VIII, 4-(m-hydroxy~henyl)-f-methyL-4-p~eridylethyl ketone)-This is a close chemical relative of pethidine. In guinea-pigs it possesses both analgetic and antitussive activitiess7, whilst in rats it is more potent as an analgesic than as an a n t i t u s s i ~ eThe ~~. results in guinea-pigs are generally more comparable to those obtained in man than those obtained in the rat12g. Trimeperidine-The Russian drug trimeperidine (Promedol, I X , 4-phenyl4-propionyloxy- 1,2,5-trimethylpiperidine), also chemically related to 101

ANTITUSSIVE DRUGS

5 1

pethidine, was tested in dogs by a method involving electrical stimulation of the vagus. I t was found to be about four times as active as codeine, but it depressed r e ~ p i r a t i o n l ~ ~ .

%


C0.E t

I

I

IVIJJ)

Me

he

Methadone-The drug methadone (Amidon, Amidone, Polamidon, Phenadone, X, 2-dimethylamino-4,4-diphenyl-5-heptanone)was first described by Eislebls7 and his results were published by the Allies after the warlea. Ph&. CH, .CHMe . NhSe,

I

CO.Et

(x-)

I t has been studied extensively as the racemate and in the form of its dextro and laevo optical enantiomers. Winter and Flatakerg6 tested methadone as an antitussive, using unanaesthetized d o p , and found its d-enantiomer active in doses of 0.5 to 1 mg/kg after oral administration. Green and Wards5 later found methadone hydrochloiide to be active in cats when tested by the method of Domenjozs4 in doses of 0.05 mg/kg. They stated that methadone had the highest antitussive activity of all the drugs tested in their series and they classified it as being eight times as active as morphine, twenty times as active as pethidine and eighty times more active than codeine. Its antitussive activity was inhibited by nalorphine. However, from tests in guinea-pigs using a sulphur dioxide aerosol induced cough, methadone was classified as a drug with mainly analgetic activities and comparatively little antitussive activityB7. Reichle and Friebc17* found &methadone more effective as an antitussive than as an analgesic in rats. I n unanaesthetized dogs, methadone was nine times more active than codeine". GusevaI4' later found that methadone was about eight times as active as trimeperidine and about thirty times as active as codeine, with a longer duration of activity; but its depressant action upon respiration was such that it was recommended for clinical use only with some reservations. Huet130 evaluated methadone by electrical stimulation of the tracheal mucous membrane of the anaesthetized cat, and found it to be better than morphine as a cough-suppressant. He also stated that nalorphine inhibited the antitussive activity of methadone, and confirmed the earlier results of Green and Warda5. The drug was also reported to have no influence upon the output of respiratory tract fluid in animals169. Methadone has been found to be a potent suppressant of experimentally 102

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induced cough in man106J19.The antitussive effect of 2.2 mg was approximately equal to that of 20 mg codeine phosphate or 7.5mg dihydrocodeinone bitartratelo6.The noted side-effects of methadone were sedation and euphoria in doses from 1-5 mg, and ataxia lasting for four to six hours with higher doses. Its antitussive effect, however, did not increase with doses higher than 5 mg. Contrary to other authors, Trendelenburg stated that methadone stimulated respiratiodo'j. Bickerman and Itkin145 investigated methadone in a double-blind study, using cough produced experimentally in human subjects by means of citric acid aerosol. Using a dose of 2-5 mg, they classified methadone among the drugs with peak antitussive activity during the first three hours after administration. Of 43 children and infants treated with 1.5-2 mg every 3-4 hours for a variety of respiratory disorders, 65 per cent gave excellent and 30 per cent fair results, with only two failures due to i n t ~ l e r a n c e l ~Rasch171 ~. conducted a double-blind clinical study on 19 patients using placebo and 10 mg of d-methadone four times a day for 3-4 days, and showed that the drug was twice as effective as the placebo. Isomethadone-An isomer of methadone, isomethadone ( X I , &dimethylamino-4,4-diphenyl-5-methyl-3-hexanone) was first prepared172in 1948.

Ph,C. CHMe.CH,-NMe,

I

CO.Et

(XI) Winter and Flatakerg6found that I-isomethadone had about forty times the analgetic activity of the rl-enantiomer, which was found to be much more effective orally than by subcutaneous injection. The authors stated that d-isomethadone was an orally active antitussive in doses of 0.5-2mg/kg. Reichle and Friebel78 found both d- and 1-isomethadone more effective as antitussive than as analgesics. Silvestrini and Maffii132,using their method of inducing cough in guinea-pigs by means of an acrolein aerosol, found no relationship between the analgetic and antitussive activities of the substances tested by them; 1-isomethadone had about four times the antitussive activity, and forty times the analgetic activity of its d-enantiomer. Dipipanone (Piperidylamidone, P$adone, XII, 4,4-d$hetyl-6-p$eridinoheptan-3one)-The compound was synthesized by Ofner and W a l t ~ n l ~ ~ . Ph,C.CH,

CO.Et I

3

SCHMe. N

I t is distinguished from methadone by having a piperidino group in place of the dimethylamino group. Its pharmacology was investigated by Green and Wards5, who found it to be forty times as active as codeine, and about half as active as methadone. Sulfamethadone (3-dimethylamino-1,I-dikhenylbutyl ethyl sulphone, X I I I )-The sulphone analogue of methadone has an analgetic effect equal to that of 8

103

Nr rru ss I VT.: DRUGS

methadone174.An improved method of synthesis has been described together with the resolution of the compound into its two optical antipodes175.The pharmacological properties of the two enantiomers were investigated by Luduena and A n a n e n k ~ lwho ~ ~ stated that the 1-isomer was much more Ph,C. CH,. CHMe .NMe,

I

SO,.Et

(XIII) effective than the d-isomer and somewhat less analgetic than I-methadone. Side-effects encountered were depression of respiration, bradycardia and miosis. The drug is an effective antitussive in dogsg7 and has only slight analgetic activityl77. Racemorphan (Dromoran, MethorFhinan, XIV, 3-hydroxy-N-methyl-morphinan) -First described by G r e ~ e l ~ it~ Jis ~classified ~ , among the drugs with

mainly analgetic and little antitussive activities87. Its analgetic activities in mice, rats and guinea-pigs have been compared with those found in manlZ9,and the results obtained in man were most closely comparable with those obtained in guinea-pigs. Comparison of the pharmacology of racemorphan and its d- and 1-components showed that the d-enantiomer had negligible analgetic activity and less respiratory depressing activity than the I-enantiomer, and was less toxic. All three forms were stated to be moderately active as antitussives. The corresponding methyl ethers were found to have similar properties, but appeared to be less potent. The d-enantiomer of the methyl ether was stated to stimulate respiration and to be active as an antitussive agentls0. Isbell and Fraser181,182 investigated the actions and addiction liabilities of racemorphan and its derivatives in man, and stated that both the I-enantiomer (levorphanol, Dromoran (U.K.), Levo-Dromoran (U.S.A.)) and its methyl ether had the miotic and respiratory depressant activities of the racemate, and the d-enantiomers were inactive in those two tests. Both levorphanol and the l-form of its methyl ether were found to be highly addictive, although the d-enantiomers were stated to be fi-ee from addiction liabilities. ProFoxyphene (XV, 4-dimethylamiiio-3-methyl-l,2-diphenyl-2-~ro~ioi2yloxybutane) -First described by Pohlarid and Sullivan1*3,it is capable of existing in two diastereoisomeric forms, of which the less soluble form has been called the ct-isomer, and the more soluble one the @-isomer. In preliminary

104

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experiments in rats, its cc-isomer was stated to have approximately one-tenth the analgetic activity of methadone after S.C. administration. In anaesthetized dogs 1-2 mg i.v. or up to 20 mg S.C. were said to cause no respiratory depression. I t was also stated that the P-diastereoisomer had no analgetic activity. Bickerman, German, Cohen and Itkin144studied the antitussive activities of dl-, d- and I-propoxyphene (presumably the ccdiastereoisomer) in healthy human subjects using citric acid aerosol to induce

0 .CO . Et

I

PhCH,.C.CHMe-CH,-NMe,

I

Ph

(XV) cough, and they found that all the drugs tested were significantly better than a placebo. A dose of 32.5 mg of I-propoxyphene had an antitussive effect approximately equal to that of 15 mg of codeine. Silvestrini and Maffii132 who investigated d- and I-propoxyphene using the guinea-pig acrolein aerosol test found that d- and 1-enantiomers were of about equal potency as antitussives, but that the d-form was more effective as an analgesic. It should he repeated at this point that all the drugs listed in the above paragraphs possess addictive liabilities, although propoxyphene is stated to be substantially less addictive than codeine. This problem has been thoroughly reviewed32.

Synthetic Antitussiue Compounds I n this section the antitussive drugs obtained by total synthesis are discussed in the chronological order in which they appeared in the literature covered by this review. Piperidione (Sedulon, XVI, 3,3-dicthyl&eridine-2,4-dione) -This compound was first described in a German patentlS4.

hot tinge^-185 found that in mice and rabbits, piperidione was a drug with sedative and hypnotic activities, and a markedly low toxicity. When tested in 340 patients with various respiratory disorders, excellent results were reported in over 300 cases185. The drug in 100 mg doses is about as effective as an antitussive as 20 mg codeine, but many patients are distinctly sedated by this dose, and the drug inhibits respirationlo6. Jacobsls6 also evaluated 105

ANTITUSSIVE DRUGS

the drug in 25 cases of advanced bilateral pulmonary tuberculosis and reported that all patients experienced relief. 2-Amino-6-methylheptane (2311)-It was synthesized by Rohrmann and Shonlels

'.

Me,CH. (CH,) 3 . CHMe . NH, (XVII) Ornstonl88 treated 90 patients with minor respiratory disorders by means of a special inhaler, and reported 81 per cent success, with no evidence of irritation or addiction, but an occasional occurrence of nausea. Other ~ o r k e r s ~ ~have Q J ~also 0 reported marked relief in about 70 per cent of patients with upper respiratory tract infections ; but patients complained about the unpleasant odour or taste of the drug, which caused gagging, initial coughing, or a burning sensation in the throat and chest. Sodium Dibunate-This compound (Sodium 2,6-di(t-butyl)naphthalenesulphonate, Becantex, Becantyl, Linctussal, L- 1633, XVIII) was first described as an industrial wetting agentlS1. Recent worklQ1aindicates that sodium dibunate is a mixture of sodium 2,6- and 2,7-di(t-butyl)naphthalene4-sulphonates.

I

SO,Na

IXVIIII

I t possesses antitussive activity in the dog, with little influence upon respiration volume but some increase in respiratory rate; it has low spasmolytic activity, and low toxicity1I3. There was however no dose-response relationship in guinea-pigs exposed to sulphur dioxides7. S a l e r n ~ using ~~~, guinea-pigs similarly treated and cats and rabbits in which cough was eIicited by electrical stimulation or by inhalation of saline-ether aerosol, reported that laryngeal cough was diminished with doses of about 1 mg/kg, and abolished with higher doses. As a centrally active antitussive it was not only effective in inhibiting cough at 10 mg/kg i.v., b u t it also raised the threshold value of stimulation62. Using the method of D~menjoz'~, its EDso in the cat has been estimated as 4.4 mg/kg i.v., with a duration of effect of 70 minutes after double this dose141. I t is interesting to note that the antitussive activity of aromatic sulphonic acids is not limited to the above compound : in a structure-activity studylQ3,a comparison was made of sodium 2,6-di(t-butyl)naphthalenesulphonate with the corresponding 2-t-butyl derivative and with ptoluenesulphonate. Using doses of 0.0436 millimoles/kg in the guinea pig . to inhibit cough elicited with ammonia, all three substances gave about the same degree of reduction in cough frequency, and antitussive activity did not reside in the t-butyl group, nor in the naphthalene nucleus, but rather in the sulphonic acid moiety.

106

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Clinical studies using a daily dose of 90-240mg gave good results in reducing the frequency of coughing attackslg4,in cases of severe respiratory diseaselg5,and in reducing the frequency of cough in patients with neoplasms of the respiratory tractlg6.Simonlg7found 90-120 mg somewhat less effective in patients with pulmonary emphysema, but Cremoncinil98 achieved notable success with doses of 30-90 mg per day in infants and children, particularly in cases of pulmonary tuberculosis and of pertussis. A molecular complex of the closely related 2,6-di(t-butyl) naphthalenedisulphonic acid with l-dimethylamino-3,3-diphenylhexane-4-one(normethadone) was found to be about as active as codeine in the rat, and to have a similar therapeutic index79. A clinical trial carried out by Schmidtlg9gave satisfactory results, with no influence of the drug on blood pressure, haemogram, urine analysis, digestive functions, blood sugar levels, or appetite. The closely related ethyl ester of 2,7-di(t-butyl)naphthalene-4-sulphonic acid (2,7 ethyl dibunate) has also been found to have antitussive activitieslgga and in the dog or guinea-pigs4. in the Bentonatate-The first description of benzonatate (nonaethyleneglycol monomethyl ether 6-n-butylamino-benzoate, Benzononatine, Tessalon, KM 65, AGB) was in a series of U S . patents issued to Matter2w. These cover esters of polyethyleneglycol monoalkyl ethers with substituted p-aminobenzoic acids, of the general structure ( X I X ) . In this formula, R represents

hydrogen or a lower alkyl group of 1-6 carbon atoms, n is an integer from 7-50 inclusive, and R1 represents the n-butyl group, an alkyl group of 5-7 carbon atoms, or a cycloalkyl or oxa-alkyl radical with 4-7 carbon atoms. The title compound may be represented by formula X I X in which R = Me, n = 9, and R1= n-butyl. Bucher66 stressed the importance of the pulmonary stretch receptors in the mechanism of cough, therefore with this in view, compounds which selectively anaesthetize pulmonary stretch receptors and tactile receptors were needed to be tested; a t the same time it was realized that such compounds must be comparatively inactive against thermoreceptors which have their afferent pathways in thin nerve fibres of slow conductance. Accordingly chemical combinations of a n efficient local anaesthetic group with a suitable substance possessing selective affinity for myelin were tried out2"'-'.p-(nButylamino) benzoic acid was selected for the former, with polyethyleneglycol monoalkyl ethers for the latter. A study of the relationship between chemical structure and biological activity was made using rabbits for determining activity upon pulmonary stretch receptors, the guinea-pig ear test for influence upon tactile receptors, and the well-known mouse tail test for determining effects upon thermoreceptors. The parent substance 107

ANTITUSSIVE DRUGS

amethocaine (Tetracaine, /&dimethylaminoethylp - (n-butylamino) benzoate) was highly effective upon stretch receptors and thermoreceptors but had little effect upon tactile receptors. Investigating the compounds of formula ( X I X ) in which R and R1were kept constant as methyl and n-butyl groups respectively, and n was varied from 6 to 18, the desired maximal activities upon pulmonary stretch receptors and tactile receptors together with minimal activity upon thermoreceptors were found to occur with n = 9. Tests for antitussive activity of the compound with n = 9 in the cat by the method of K r ~ e p f i confirmed l~~ Bucher’s hypothesis, the average thre.;hold value for inhibition of coughing being found as 0.3 mg/kg. Bucher’s pharmacological investigations xvere confirmed by a clinical study of structure-activity relationships carried out by HerzogG7,who used similar compounds where n equalled 6, 9 and 18. I n a preliminary trial, the compound with n = 18 proved to be active, while the compound with n = 6 was incapable of inhibiting cough or of easing respiration, and the best results were again obtained with the compound where n = 9. The compounds were then evaluated in cases of pleurogenic and bronchogenic cough, and satisfactory results were obtained in over half of the cases. I n these trials, the compound with n = 9 was found to be effective in doses of 5 mg i.v., 50-100 mg P.o., or 5-10 mg S.C. The onset of action was apparent within two minutes after i.v. injection, with an average duration of effect of about two hours, and was apparent five to ten minutes following S.C. or oral administration, with the effect lasting from two to ten hours. Particularly noticeable were the exceptionally low toxicity of the compound and the absence of cardiovascular side-effects, such as those encountered upon i.v. injection of procaine. After the success of benzonatate ( X I X , n = 9, R = Me, R1= n-butyl) a series of compounds with the general structure X X was synthesizedzo1in which R represents hydrogen or a lower alkyl group, R’ represents hydrogen, lower alkyl, or loww alkoxyalkyl, X stands for hydrogen, hydroxy, alkoxy, cycloalkoxy, alkoxyalkoxy, or a saturated oxacycloalkylalkoxy group, and Y represents an alkyl, cycloalkyl, oxacycloalkylalkyl, cycloalkylalkyl, or an alkoxyalkyl group, with n being varied from n = 7 to n = 17.

Although the above compounds were described as having antitussive and local anaesthetic activities which extended in some cases also to the pulmonary stretch receptors, none of them appear to have attained clinical importance. One of the difficulties in obtaining the compounds in the pure state has recently been resolved through an improved process for the preparation of pure polyalkylene glycol etherszo2. One of those ethers, dodecylpolyethylene oxide ether (DOR 9/3), of the average composition 108

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C,,H,,(O~ C2H,). .OH with n = about 9, had been shown earlier to have important inhibitory effects upon pulmonary stretch receptor^^^^^^^^. After the work of BucherG6 and HerzogG', benzonatate became probably the most thoroughly studied drug in the antitussive field. Bein and Bucher'O compared the drug with a number of well-known local anaesthetics, antihistaminics, and antispasmodics ; they found it to have the highest activity of all drugs tested upon pulmonary stretch receptors and in conductance anaesthesia ; they found also high activity in inhibiting central spinal polysynaptic reflexes, and moderate activitiea in infiltration and local anaesthesia. I n a comparison of the drug with local anaesthetics, only benzonatate was active upon both pulmonary stretch receptors and contact receptors. Moreover, it is more potent as a n antitussive in the cat than three of the five reference compounds205. Silvestrini and Maffii132 found benzonatate highly effective in inhibiting acrolein-induced cough in the guineapig, as well as in the cat by the method of Domenjoz7*, and somewhat effective in the dog, following faradic stimulation of the trachea. Guth and Goldenberg115 investigated its activity in the trachea-clamping reflex in the dog, and discussed its probable mode of action. The pharmacology of benzonatate in human subjects was studied by Marx20G,who investigated the influence of the drug upon respiratory dynamics in healthy subjects and patients with emphysematous bronchitis. He reported that it had no spasmolytic activity, no central respiratory depressant effect, and no influence upon resting respiration. Its action appeared to be peripheral, and it improved forced respiration in patients, causing an increase in respiratory reserve. Shane, Krzyski and C ~ p p l ' ~ found that 100mg benzonatate was more than twice as active as 30mg codeine in reducing frequency of cough. Tiffeneau's methodl12 was used by Gregoire, Thibaudeau and Comeau207 to show that benzonatate in doses of 10 mg i.v. reduced coughing. The first clinical study of benzonatate was published by Giuliano and RossaZ08,who reported major successes in coughs associated with various respiratory conditions. Later, NaegeliZo9reported success in cases of irritative and pleurogenic cough. Other favourable Success clinical investigations of the drug have been rep0rtedl50~~07~210-~~~. has also been obtained in the treatment of cough associated with pulmonary tuberculosis20g~z19-222. I n infants and children suffering from various respiratory diseases, daily doses of benzonatate (0.5-1.5 mg/kg i.m., or 4-10 mg/kg rectally, or 4-8 mg/kg orally) gave very satisfactory results, especially in cases of p e r t ~ s s i s ~ ~ 3 -Equally 2~~. satisfactory results in the treatment of pertussis were reported when the drug was given in the form of an aerosol in daily doses of 10-40 mgZZ7. The drug was also used successfully in inhibiting cough associated with surgical procedures, such as extrapleural pneumothorax228,tracheotomyZl5, bronchospirometry, bronchoscopy, bronchography, laryngoscopy, and oesophagoscopy207~229. Husen221,and also S ~ r i a nfound i ~ ~ that ~ it was ineffective in bronchoscopy, but Diamant231 used it to inhibit cough during surgical operations on the ear. I n pulmonary emphysema, benzonatate caused a n improvement in 40-80 per cent of although Simon233,in a double blind study on patients with asthmatic bronchitis, had found no significant differences between hydrocodone, benzonatate, 109

ANTITUSSIVE DRUGS

and a cough syrup containing ephedrine, ammonium chloride, and elixir terpin hydrate which has been used as the vehicle for the two drugs. The Council of the American Medical Association reviewed the literature on benzonatate, commenting on its peripheral and central action, on the low incidence of side-effects, the reported increase in depth and rate of respiration, and the low toxicity of the drug. The dosages suggested were 100 mg three to six times per d a ~ ~ ~ 4 . Basic esters of C-substituted phenylacetic acids Caram$hen Ethanedisulphonate-The free base of the above structure and its hydrochloride salt were first described as therapeutically useful R

I

and the hydrochloride has since been widely used as a parasympatholytic agent (Panparnit, Parpanit). Subsequently, the structure was modified to include the isopropylmethylaminoethyl ester236and a series of compounds23i represented by the above formula ( X X I , R or R1 = H, Me, OMe; R 2 = NEt,, morpholino, or piperidino), but none of those compounds has attained clinical importance. The antitussive properties of the ethanedisulphonate salt23sof the free base (Taoryl, Toryn, 2-diethylaminoethyl l-phenylcyclopentanecarboxylate, X X I , R = R1 = H, R2 = NEt,) were first recognized by Domenjozi4. Toner and Macko103, using Domenjoz’s method, found it to be less effective than codeine but with a longer duration of activity. The central effects of caramiphen were studied at doses of 2.5-6.0 mg/kg i.v., which reduced cough and had little influence upon respiration62. Huet130 however found it to be ineffective as an antitussive, even in high doses. Bein and BucheriO reported that it was weakly active upon pulmonary stretch receptors, central spinal polysynaptic reflexes, and in conductance anaesthesia, and of very low activity in local and infiltration anaesthesia. On the other hand, Roth2B9reported it to have about 70 per cent of the activity of codeine. Doses of 10 mg of caramiphen ethanedisulphonate inhibited cough for 3-5 hours in 60-70 per cent of patients with various respiratory disorders, and in over 80 per cent of cases o f p e r t u ~ s i s ~ A~double ~. blind study on 26 patients in a tuberculosis sanatorium against placebo, codeine, and hydrocodone, showed that it was more effective than placebo but less effective than the two other drugs; doses of 30 mg per day caused drowsiness and dizzin e s in patientsZ4l.In a double-blind study on 120 patients, doses of 10 mg

110

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were less effective than 15 mg codeinez4z.H ~ d s o n ~stated 4 ~ that large doses (60-80 mg) were useful when given shortly before bronchoscopy. I n a series of 100 patients with dry or non-productive cough of long duration, Snyder244 obtained relief in 88 cases after treatment with 40-60 mg per day, but he also observed 6 cases of mild nausea. The compound may have a sedative effect upon the bronchi ole^^^^. Two compounds which are chemically closely related to caramiphen should be briefly mentioned a t this point. Both correspond to the general

formula ( X X I I ) , which differs from that of cnramiphen essentially in having the phenyl and the cyclopentyl groups of the latter replaced by two cyclohexyl rings. Dicyclomine (Bentyl, Bentylol, Merbentyl, Dicyclovirine, Wyovin, XXII, K = NEt,)-This is a well-known antispasmodic drug. Boissier25, referring to unpublished work from his own laboratory, found that it possessed considerable antitussive properties. Dihexyvirine (Spasmodex, Metaspus, X X I I , R = jiperidino)-Also well known as a powerful spasmolytic, it was included by Boissierz4in his recent review of synthetic antitussives. He stated, without giving any details, that it possessed antitussive activityz5. Curbetupentune-Structurally closely related to caramiphen (XHZ), Carbetapentane (Toclase, Tuclase, PentoxyvCrine, Atussil, 2-(diethylaminoethoxy)ethyl I-phenylcyclopentyl-I-carboxylate,XXIII: R R1= (CH,),,

+

n = 2, R2 = NEt,) differs from it only in having a 2-(diethylaminoethoxy)ethyl instead of a 2-diethylaminoethyl side chain. I t was first described by MorrenZ46,who also synthesized a number of close analogues in which n = 2 and R2 = NEt, were kept constant, viz. (XXZIIb) : R R' 111

+

ANTlTUSSIVE DRUGS

+

= (CH,),; (XXZZIC): R R1 = (CH,),; (XXIIId) : R x R1 == CH,. CH,. 0 .CH,. CH,; (XXZIIe); R = Ph, R1 = H; (XXZIIf): R cyclohexyl, R1 = H ; (XXIIZg): R = 2-thienylmethyl, R1 = H; (XXZIZh): R = 2-furylmethyl, R1 = H. Some of the above compounds, together with =y

a number of additional analogues corresponding to the general formula

( X X I I I ) , and two additional compounds in which the 2-(diethylaminoethoxy) ethyl group of carbetapentane is replaced by 3-diethylamino- 1methylpropyl (XXZV) or by 1,3-bis(diethylarnino)propyl ( X X V ) groups respectively, were investigated for their antitussive activities143.Using the method of Domenjozi4, and expressing the activities of the compounds as percentages of the antitussive activity of codeine, the results shown in Table 3.4 were obtained : Tuble 3.4. Antitussive activity of carbetapcntane analogues Antitussiue activity

n

Compound

(codeine

XXIIII,

<75 <75

XXIIIfl XXIIIk XXIIIln XXIIIC

150

xxm xxmj

XXIv

xxv

=

100)

75

<75

(CH,), (CH,),

i

211.5-37.5 (75

CHMe.(CH,),.NEt, CH(CH,. NEt,) 2

<75

From the above results, carbetapentane (XXIIIa) was the compound of choice in this series. Moreover, it was found to be of low oral acute toxicity (230 mg/kg mouse, and 830 mg/kg rat) and of low 'chronic' toxicity: a group of mice survived daily oral doses of 100mg/kg for 30 days. I t caused a transient fall in blood pressure, it possessed a weak antispasmodic effect, but its local surface and infiltration anaesthetic effects were stated to be 2.4 times and three times those of procaine re~pectivelyl~~. Additional pharmacological studies239showed that the antitussive effect of the drug is 150 per cent that of codeine, with a similar duration of effect, when determined by D ~ m e n j o z ' smethod. ~~ Huet130 found that the drug has negligible antitussive effects in dogs, but other workers140,using a similar technique, reported that 1 mg/kg i.v. inhibited cough considerably more than 4 mg/kg i.v. of codeine. The first clinical study OF the drug was completed by D e p ~ o r t e r who ~~~, used daily doses of 30-100 mg. He stated that it was superior of codeine syrup and codeine plus morphine syrup in the treatment of cough due to mechanical irritation, that it gave excellent results in cases of productive cough, and that it was ineffective in cases of asthma. Parish248,using daily doses of 25-180 mg in the form of tablets or syrup, also obtained excellent results, but noted five cases of slight drowsiness, two of allergic rash, and one of nausea in a series of 44 patients. Carbetapentane has also been recommended as an aid in anaesthetic procedures such as b r o n c h o s ~ o p yand ~~~~~~~

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bronchial ~ a t h e t e r i z a t i o n ~R~ l .~ t found h ~ it ~useful ~ in cases of bronchiectasis, bacillosis, pulmonary neoplasms, and also in asthma. Carter and Maley252, using daily doses of up to 150 mg, found that cough was reduced or abolished in 91 per cent of 557 cases. Thus, carbetapentane is an antitussive drug of low toxicity and satisfactory efficacy, with a low incidence of side-effects, none of which appear to have been serious. Nevertheless, it was apparently withdrawn from the market in Britain in 1959, although it is still available in the U.S.A. and in Canada.

Esters of C-substituted phenylacetic acids Compounds have also been prepared, corresponding to the general formula ( X X V I ) , in which R1 and R2 are not linked with each other as in caramiphen or carbetapentane, but represent monovalent alkyl, aryl, or heterocyclic radicals and in which A represents an alkyl or alkoxyalkyl radical usually substituted with a basic group.

K'

I

Ph .C * CO . OA

I

R2

(XXVI) 2'-Diethylaminoethyl 1-Phenylbulyrate ( X X V I , R1= Et, R2 = H, A = was first prepared by H a l ~ e r n , ~Engelh~irdt,~* ~. found that the drug possessed much less spasmolytic activity than the corresponding diphenylacetate (R1 = Ph), while its bronchodilator activity was superior to that of ephedrine. The toxicity of the compound was exceptionally low. I n tests for antitussive activity, 0.3 mg of the drug given intraduodenally were about as effective as 0.4 mg codeine, and it potentiated the antitussive used the drug in the combination preparation effects of codeine. 'Solgettes' on 150 patients with various upper respiratory tract infections; 92 of these patients reported themselves improved while only 5 reported side-effects. P'-n-Butoxyethyl 1-N-piperidinodipheigJlacetate-This compound ( X X V I , R1 = Ph, K2 = piperidino, A = CH, . CH, . OBu) was synthesized as one of a series of analogous compounds in which the terminal n-butyl group was replaced by methyl, ethyl, or n-hexyl I t has apparently the highest antitussive activity in this series, with central sedative and local anaesthetic activities. As a spasmolytic agent it was found to have 65 per cent of the activity of papaverine. I n a subsequent patent257,it was described as being 2-3 times more effective as an antitussive than codeine. No clinical details have become available to date, but the compound is interesting from the structural point of view in having the basic group located in the acid moiety rather than in the alcohol side chain. Introduction of a second basic group, in the usual terminal position on the side chain, apparently destroys antitussive activity: the tertiary acid addition salts of the latter compounds have spasmolytic and central sedative properties, while the quaternary salts have curare-like a c t i v i t i e ~ ~ ~ ~ - ~ " .

CH, . CH, .NEt,)-It

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ANTITUSSIVE DRUGS

Esters of C-substituted diphenylacetic acids Compounds were prepared by Polezhaeva261 corresponding to formula ( X X V I ) with R1 = Ph, R 2 = H, Me, Et, OH, OPr, A = CH,‘CH,.NR3, or CH,. 0 .CH, .CH,. NR3, or CH, CH, . O . CH, .CH,. NR3, with R3 = Me, Et, Pr, Bu, also thioesters of the same structure, e.g. Ph,CR2.C0.S. CH,. CH, . NR3,. They were then tested for antitussive activity by two 74. One of the fifteen compounds prepared (2-diethylaminoethyl benzilate, XXVI, R1= Ph, R2 = OH, A = CH, . CH,. NEt,) was found to be more active than codeine or benactyzine, although later it was reported to be ineffe~tivel~l. Oxeladin-This compound (Pectamol, 2’-( 2-diethy1aminoethoxy)ethyl 1, 1-diethylphenylacetate, XXVI, R1= R2 = Et, A = CH, . CH, . O . CH, . CH, .NEt,) was first prepared by Petrow, Stephenson and Wildz6,. Pharmacological studies were carried out by David, Leith-Ross and V a l l a n ~ e , ~ ~ , who selected the compound as the most promising in a series in which the NEt, group had been varied to include NMeEt, NEtPr, NBu,, N(C6H13),, pyrrolidino, piperidino, and A3-piperideino groups. Its antitussive activity, determined by Domenjoz’s method74,was found to be about equal to that of carbetapentane, and slightly less than that of codeine. Its acute toxicity was similar to that of carbetapentane, both compounds being about 2-4 times as toxic as codeine. Oxeladin was also found to be about twice as active as procaine as an infiltration anaesthetic. Huet130 reported that its antitussive effect was negligible, but Kohli, Gupta and Bhargava141found it to be slightly superior to codeine, with an ED,, of 1.22 mg/kg i.v. I n a clinical trial on 35 children, RobertszB4reported success in 26 cases, 4 failures, and one case of allergic side-effects. Isoarninile-The compound (Peracon, Dimyril, 2-495,4-dimethylamino-2isopropyl-2-phenylvaleronitrile,XXVII, R = Pri, A = CH,.CHMe, B = NMe,, R1 = H) may be regarded as being somewhat related to the group of compounds discussed above, being formally derived from phenylacetonitrile (a-isopropyl-a-(~-dimethylaminopropyl)phenylacetonitrile). An isomer +

of isoaminile in which A = CHMe . CH, was first described, together with a number of closely analogous compounds in which K = 1-methylpropyl or a-methylbenzyl, A = CH, . CH,, and B = dialkylamino or piperidino, with R1 = hydrogen or m - m e t h o ~ y ~ 6 ~These - ~ ~ s . compounds were stated to be powerful analgesics with spasmolytic activity equal to that of papaverine. In addition, R ~ r i g synthesized ,~~ a series of compounds which were stated to have diuretic activity. In these the phenyl group in ( X X V I Z ) was replaced by the fi-methoxy- or the p-hydroxybenzyl group, with R = p-methoxy- or p-hydroxyphenyl, A = CH,.CH,, and B = NEt,. Further, Moffett and 114

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AspergrenZ7Odescribed another series of compounds with the general structure (XXVII) in which R = Ph, Pri, m- or p-ClC,H,, A = CH,. CH,, and B = NEt,, piperidino or substituted N-heterocycles, and found them to possess some anticholinergic activity. Basically substituted diphenylacetonitriles (XXVII, R = Pli, R1= H, A = CH,. CH,, CH, .CHMe, or CHMe . CH,, and B = NMe,, NEt, or piperidino) had been characterized much eai as having atropine-like activities. The antitusaive activity of isoaminile was discovered by K r a ~ s e ~who ~,, used cough elicited by means of electrical stimulation of the tracheal mucosa of guinea-pigs under urethane anaesthesia. Its ED,, was found to be 5,4mg/kg i.v. (codeine 7 mg/kg i.v.) Its analgetic activity was low, and respiration was slightly inhibited by doses of 5 mg/kg. Acute toxicity tests in mice gave LD,, values of 65 mg/kg i.v., 240 mg/kg s.c., and 720 mg/kg p.0. I n a test for subacute toxicity in mice, animals survived daily oral doses of 20 mg, but other workers273found livcr damage in dogs and rats after daily oral doses of 20 mg/kg for 4 weeks. Isoaminile caused a transitory drop in blood pressure, did not potentiate barbiturate hypnosiq, and was ineffective in preventing leptazole shock274. Christoffel and K ~ l b e r g found , ~ ~ the drug to be effective in human subjects in reducing cough induced by inhalation of 7.5 per cent citric acid aerosol. Clinical trials by the same authors275with daily doses of 90-320 mg showed that the drug became effective 15-20 minutes aftcr oral administration, and that its effect lasted for 4-5 hours. No toleiance developed, and the drug was reported as being neither habit-forming nor addictive. Isoaminile was also reported to have no effects upon haemogram, urine analysis, blood pressure, liver function, nor respiratory function. Isoaminile as a cough suppressant gave good to excellent results in patients suffering from pulmonary tuberculosis and diseases of the respiratory t r a ~ t ~ ' ~ - undesirable ~*,; side-effects were rare or absent. I n summing up the clinical evidence, isoaminile appears to be a uaeful antitussive drug, about as effective as codeine, and with a low incidence of side-effects. R- 1132 (4-( 4-phenyl-4-ethoxycarboi2_y~ieridiizo) -2,2-daphenylbutyronitrzle) Closely related to isoaminile, it may be represented by formula (XXVIZ)with

K

=

Ph, R1- H, A

=

CH2.CH2,B

=

N

The compound was synthesized in 1959 together with 17 close congeners, in which the ester group in B and the length of the caibon chain in A was varied283.I t was found to be among the most active compounds in inhibiting gastrointestinal motility in mice and in rats. Morris and Shane284stated that the drug had slight analgetic activity, and no parasympatholytic effects. They investigated its antitussive action in a double blind study on healthy volunteers by the citric acid aerosol methodlog. They found that 5 mg of R-1132 was about two-thirds as effective as 30 mg codeine in 17 subjects. Doses of 15 mg of R-I132 gave inhibition of cough in four subjects and reduction in two others, but two complained of side-effects, oiz. dizziness, headaches, and lassitude. 115

ANTITUSSIVE DRUGS

Chlophedianol-The compound, chlophedianol (Detigon, Eletuss, Ulo, SL-501, 1-o-chlorophenyl-3-dimethylamino1-phenylpropanol- 1, XXVIII, R = o-C1C6H,, A = CH,. CH,, B = NMe,) may be regarded as somewhat related to the above compounds of the general structure ( X X V I I ) and may be formally derived by replacing the nitrile group in ( X X V I I ) by a hydroxyl group : K

I

PhC. A . B

I

OH (X'YVZZI) This class of compounds with R = alkyl, cycloalkyl, or aryl, A = CHRl. CH, (R1= H, alkyl, or cycloalkyl), and B = dialkylamino, was first synthesized and described as a n t i s p a s r n ~ d i cand ~ ~ ~the title compound was then found to have antitussive propertieszs6. Gosswald2*7 made a pharmacological study of some 65 compounds in the above series and selected 8 of them for detailed investigation of their antitussive activities. He obtained the results given in Table 3.5 using guinea-pigslog. Table 3.5. Relative antitussive activities of compounds or structure XXVZZZ with A = CH,.CH, R

Ph

B

I

I'h

NH, NMe,

-_

Relative

Antitussive Activity

0

I

60

lo-CIC,H,

! ~

NMc,

NMe,

100

20

~

I

NMe,

40

The antitussive ED,, of chlophedianol was found to be 20 mg/kg S.C. In experiments on dogslO1, the drug proved to be as potent as codeine in doses of 5 mg/kg p.0. or of 2 mg/kg S.C. In rabbits, chlophedianol had no influence upon respiration a t 5 mg/kg i.v., while codeine or morphine at the same dose level caused definite depression. Guinea-pigs treated with 20 mg/kg S.C. daily for eight consecutive days showed no decrease of antitussive response. Its acute subcutaneous, intravenous, and oral toxicity in dogs, cats, rabbits, guinea-pigs, rats, and mice was found to be generally lower than that of c ~ d e i n e ~ Boyd ~ ~ ~ and ~ * Boydzsg ~. found that chlophedianol diminished the output of respiratory tract fluid in rabbits and in cats, and produced at the same time a decrease in the incidence of mucous pledgets. There are many favourable clinical reports of the use of chlophedianol as a n antitussive2s*~z90-z98 in patients suffering from bronchopneumonia, chronic cough, pulmonary neoplasms, and in postoperative conditions. Summarizing the above results, the drug appears to be a useful antitussive, effective in doses of 20-30 mg given 3-5 times per day, with a durntion of effect of a single dose of 3-5 hours and a low incidence of side-effects. 116

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Tussukal ( Tusucal, Tussi1ax)-This is a preparation of the adrenergic p-hydroxyephedrine (Suprifen, 10 mg) , with the active antitussive ingredient, 40 mg of the preparation Hoe 10682 (4964 U; 1, 1-diphenyl-2-piperidinopropanol-I, XXVIII, R Ph, : A = CHMe, B = piperidino). I t differs from chlophedianol with respect to three points: the basic group B is piperidin0 instead of dimethylamino; its position is shifted from the 3- to the 2position in the propanol chain; and R is a phenyl instead ofan o-chlorophenyl group. Hoe 10682 was first prepared by Stein and LindnerZg9,who also described a series of related compounds in which R is a phenyl group substituted with halogen, hydroxy, lower alkyl, lower alkoxy, or benzyloxy groups, and in which B represents a pyrrolidino, piperidino, 2-methylpiperidino, morpholino, or a tetrahydroisoquinolino radical. This series was subsequently extended by Lindner and Stein300 who made a detailed study of the relationship between antitussive activity, toxicity, and chemical structure, using an antitussive testing technique similar to that of Domenjoz7*. Compounds with the general structure ( X X I X ) were investigated. R3R4 Rl-C.

I I

CR5

(XXIX) The parent compound, Hoe 10682 (R1 = R 2 = Ph, R3 = OH, R4 = piperidino, R5 = Me, R6 = H), was arbitrarily assigned the antitussive activity = 1 and the toxicity = 1, and the following groups of compounds were described : (a) With R1, R3, R4,R5and R 6 representing the same groups as in Hoe 10682, and substituting the phenyl group R2 with mono- or di-hydroxy, mono- or di-lower alkoxy, chloro, or lower alkyl radicals, or replacing it by a 3-pyridyl, cyclohexyl, 6-biphenylyl, lower alkyl, or a benzyl group, 20 compounds were obtained of which only the one with R2 = p-biphenylyl had a higher antitussive activity, but also a much higher toxicity, than Hoe 10682. ( b ) In a second group of 10 compounds the OH group R 3 was esterified to include 8 different esters and 2 compounds in which the OH group had been replaced by the diethylamino or piperidino group. The p-aminobenzoate of Hoe 10682 proved to have four times the antitussive activity of the parent compound, with a similar toxicity. ( c ) Only the basic group R4was varied in this group of 13 compounds, to include mono- and di-lower alkylamino, pyrrolidino, 2-methylpiperidino, morpholino, tetrahydroisoquinolino, and cycloalkylamino radicals; but none of those compounds exceeded Hoe 10682 in antitussive activity. ( d ) Finally, 21 compounds were described in which first R5 or R6 were varied alone, or together with one, two, or three of the other groups in formula ( X X I X ) . In the best two compounds, R1, R2, R5 and R 6 were the same as in Hoe 10682, with the OH group in R 3 being esterified with p-aminobenzoic acid. The compound with R4 = dimethylamino had twice the

117

ANTITUSSIVE DRUGS

antitussive activity of the parent compound, and that with R4 = diethylaminomethyl had four times the activity, while both had the same toxicity as Hoe 10682. However, some of the compounds which had the highest activities upon i.v. injection were found to be no more active than the parent compound upon oral administration, and further investigations were therefore restricted to that compound. The antitussive ED,, of Hoe 10682 was reported3o0to be 2 mg/kg i.v., or about one-half the potency of codeine. No difference in activity was found between the racemate and the optically active enantiomers of the compound. I t had no analgetic activity in doses as high as 200 mg/kg s.c.; while it had no effect upon respiration in intact rabbits or cats, it caused a slight depression in anaesthetized animals. Toxic doses were found to cause convulsions, and no sedative action was noted. The drug caused slight and transient effects upon circulation, had a low degree of activity upon the autonomic nervous system, and little influence upon intestinal motility. I t had considerable local anaesthetic activity, about four times that of procaine. Acute oral toxicity was found to be low (LD,,: 750 mg/kg mouse). Sub-acute toxicity tests extended over 6 weeks in rats with doses of 10mg/kg p.o., given for five days per week, showed normal growth curves. However, guinea-pigs given the same dose S.C. over six weeks showed some evidence of liver damage. B o i ~ s i e r ~also ' ~ found the antitussive ED,, of the drug in guinea-pigs challenged with sulphuric acid aerosol to be similar to that of codeine (22 and 20 mg/kg i.p., respectively) ;he reported it to have about one-third the antitussive activity of codeine in cats by Domenjoz's method74.A closely related compound in which the piperidino group had been replaced by the diethylamino radical was found to be inactive. I n a double blind study in normal human subjects challenged with citric acid aerosol against placebo, codeine and a number of other antitussives, a 6 0 m g dose of Hoe 10682 was about as effective as 15-30mg codeine145.Clinical trials with the drug in various diseases of the respiratory systcrn showed that the majority of patients were significantly i m p ~ o v e d ~ ~ ~ ~ 302; there was no indication that the drug was habit-forming or addictive. Summarizing the above pharmacological and clinical data, Hoe 10682 appears to be a useful antitussive, with about one-quarter to one-half the potency of codeine, but additional clinical data are needed for a more complete evaluation. K A T-256-This compound (Silomat, 1-p-chlorophenyl-2,3-dimethyl-4dimethylarninobutanol-2, X X X , R1= R2 = R5= Rs= Me, R3 = H, R4 = p-Cl, n = 1) may also be regarded as being somewhat related to the compounds of the general structure ( X X V I I I ) in which the phenyl radical has been replaced by a p-chlorobenzyl group, with R = Me, A = CHMe. CH,, and B = NMe,. A series of some 300 basically substituted arylalkanols corresponding to formula ( X X X ) was synthesized by Berg303 with the following variants : R1 represented a lower alkyl group and R2was hydrogen, a lower alkyl group, an aryl or an aralkyl group including substituted aryl or aralkyl groups; R3 and R4,not necessarily identical, represented hydrogen, halogen, or alkyl, lower alkoxy, or tertiary amino groups; R5 and RGwere lower alkyl groups, or represented, together with the nitrogen atom, a pyrrolidino,

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piperidino, or morpholino group; and n was 1 or 2. The series included both the racemates and the optically active enantiomers of some of the compounds. The antitussive properties of the title compound were first recognized by Engelhorn304,who found it to be about as effective as codeine by injection in a number of different animal tests. I t was found to have little analgetic activity, and it reduced analgesia produced by codeine. Doses of 10 mg/kg i.p. caused transient sedation in cats, and 40-80 mg/kg S.C. some excitation in rats, while 3-6 mg/kg i.p. potentiated the effects of barbiturates in mice. The compound had no local anaesthetic and no bronchodiiator activities, R3

OH

I I / R' RZ

(CHZ),, ' C . C H . C H 2 . N

and apparently no action upon pulmonary stretch receptors, nor upon afferent or efferent pathways of the cough reflex. This indicated the central antitussive action of KAT-256. The drug was also found to stimulate respiration, and to antagonize the respiratory depressant activity of morphine. The acute toxicity of the drug following i.p., s.c., or oral administration to mice was similar to that of codeine. Chronic toxicity tests in rats treated with 50 rng/kg p.0. over a period of six months showed no pathological changes upon gross or histological examination. Riebe1305 evaluated the drug clinically in 91 patients with pulmonary tuberculosis or bronchitis, as well as in cases of irritative cough following bronchoscopy, bronchography, or pneumothorax. Treatment consisted in 2-3 daily doses of 30-40 mg, supplemented by a single dose of 120 mg at night in very severe cases. Results obtained indicated that the drug was about as effective as codeine, but the absence of side-effects such as respiratory depression, drowsiness, nausea, allergic reactions, constipation, or influences upon circulation, were noted. Prolonged treatment gave no indications of development of tolerance nor of habituation. Expectoration was not inhibited, and careful spirometric investigation on 50 patients showed no adverse influences of the drug upon respiration. Summing up the clinical and pharmacological evidence, KAT-256 (Silomat) appears at the present preliminary stage to be a promising antitussive drug, about as effective as codeine.

Thiofihene derivatiues Thiophene derivatives related to the general structure ( X X V I I I ) , i.e. basically substituted 1,1-di- (2-thieny1)alkan-1-01s ( X X X Z ) and their corresponding alk- 1-enes ( X X X I I ) obtained by dehydration, were synthesized by Adamson306 with R = H, Me, Et, Pr, and NR1R2 representing NH,, NHEt, NHBu, NMe,, NEt,, NPr,, NMe .CH,Ph, pyrrolidino, piperidino, or morpholino groups. The carbinols ( X X X I ) were described as having antispasmodic and local 119

ANTITUSSIVE DRUGS

anaesthetic activities, and the alkenylamines (XXXZZ), were, moreover, found to be powerful analgesics, with the order of potency of morphine307; the dextro enantiomers being more potent than the laevo forms308.Compounds of type ( X X X I ) in which the hydroxyl and amino groups are separated by only two carbon atoms have also been synthesized30s.Antitussive properties were discovered in 1955 in some of the above compounds as follows: Thiambutene-Green and Ward*, reported thiambutene (3-diethylamino171-di-(2-thienyl)but-l-ene, XXXIZ, R = Me, NR1R2 = NEt,) to have an antitussive ED,, of 0.2 mg/kg by Domenjoz’s method74.The drug was stated to have an addiction liability similar to that of morphine310.

Ohton-The 3-dimethylamino analogue of Thiambutene (XXXZZ,R = Me, NR1R2 = NMe,), was studied by Kaseg7in dogs and found to inhibit 60 per cent of cough at doses of 3 mg/kg for 60 consecutive days, while 0.8 mg/kg morphine inhibited cough by 90 per cent on the first day, but had no more effect on the tenth day. The drug appeared to cause 3-Piperidino- 1,I-di( 2-thienyl)but-I-ene-The 3-piperidino analogue of Thiambutene (XXXZI, R = Me, NR1R2 = piperidino) was stated to be a potent antitussive drug312. Its d-enantiomer had five times the antitussive and twice the analgetic activity of the 1-form313. I n a clinical trial on 113 patients with pulmonary tuberculosis or bronchitis, a 6 mg dose of the racemate or 3 mg of the d-form proved to be about as effective as a 20 mg dose of codeine3I4. Pipendyl methane (4-di-(2-thienyl)methylene-1-ethyl-piperidine-This compound is related to compounds of the general structure ( X X X I I ) ,e.g. to 4-diethylamino-], I-di-(2-thienyl)but-l-enein which one of the two ethyl Xroups on

the nitrogen had bcen linked back to carbon atom 2. Its structure might be represented by formula ( X X X I I I ). I t was claimed as one of a series of closely related compounds with antispasmodic, antihistaminic, and analgetic activities315.When 40-60 mg per day of the drug was given to 16 patients suffering from pulmonary tuberculosis, marked improvement was obtained in 10 patients but higher doses caused undesirable side effects3l6.

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3-Di-(2-thienyl)methylene-1-methylpiperidine ( AT-327)-A lower homologue of Pipendyl Methane in which the point of attachment has been shifted from the 4- to the 3-position on the piperidine nucleus, it was found to be more potent than codeine as an antitussive in dogs, about equipotent in cats, and less toxic than codeine in mice317.Favourable results were also obtained in a clinical trial in 45 patients. The drug was examined in 31 patients with pulmonary tuberculosis and found to be a satisfactory antitussive with almost no side effects318. KasC and Yuizono3lgcarried out an extensive structure-activity study in a series of 53 compounds analogous to analgesics, to related non-analgesic structures, to chlorpromazine derivatives, and to adrenergic amines, including a number of compounds of the general structures (XXXZ) and ( X X X Z I ) with at least two compounds in each class containing piperidino groups. The compounds were tested for antitussive effects in dogs, cats, and mice. All compounds containing piperidino groups, with the exception of those related to adrenergic amines, were found to possess antitussive activity independent of analgetic potency. N-B- (1,2-Diphenylethoxy)ethyl-N-trimethylammoniumbromide (Lysobex, Sedobex, TDBr)-This may also be regarded as being somewhat related to compounds of the general structure (XXVZZZ) in which R represents CH,Ph, A-B is replaced by hydrogen, and in which the O H group is etherified with a basically substituted ethyl group ; moreover, the basic group has been quaternized. The title compound may be represented by formula (XXXZV) (R1 = R2 = R3 = Me, X = Br) : CH,Ph

R1

+I

I

PhCH .O .CH2. CH2.NR2,XI

('YXXZV)

R3

Compounds in which R1, R 2 and R3 represent lower alkyl radicals, or R1 and R 2 together represent pyrrolidino, piperidino, or morpholino groups, with R3 = Me, and with X representing an anion, were synthesized by Suter and Kundig320and described as antitussives. The title compound was stated to have an unusually favourable therapeutic index, to be free from side-effects, and to be neither habit-forming nor addictive. P l i ~ n i e r ~ ~ l found the compound to be about one-third more toxic than codeine, but to be three times as potent as an antitussive when tested by Domenjoz's method74.Studies in the chloralosed d ~ showed g ~that ~ the drug ~ had neither bronchodilator nor bronchoconstrictive action, and that it had no spasmolytic action following challenge with histamine or acetylcholine. Its therapeutic index was reported to be 2,16 compared to 1 for codeine phosphate. The drug has been demonstrated to be useful as an antitussive in patients with various respiratory disorders323,following surgical procedures324and in patients with various diseases of the respiratory Additional clinical data are necessary for a more complete evaluation of the drug, which appears to be an effective antitussive. I t is interesting to

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ANTITUSSIVE DRUGS

note that this is one of the €ew instances in which a quaternary ammonium salt has been found to possess important antitussive activity : such activity in compounds possessing tertiary amino groups has usually been found to be destroyed, or a t least greatly reduced, after quaternization (d.65a). Amides Dextromoramide-This compound (d-N-(3-methyl-2,2-diphenyl-4-morpholinobutyryl)pyrrolidine, pyrrolamidol, R.875, Jetrium, Palfium) may be regarded as related to the above compounds of the general structure

( X X V I I I ) ,in which the OH radical had been replaced by an amide group, with R = Ph, A = CHMe. CH,, and B = morpholino. I t was first described by J a n ~ s e n ~ ~who e , synthesized over 100 compounds with the general structure ( X X X V ). Janssen found dextromoramide, the d-enantiomer of the compound with NRRl = pyrrolidino, c( = Me, ,8 = H, and NAAl = morpholino to be the most potent analgesic in that series, many times more active than pethidine, morphine, or methadone in animals. I t was twice as active as the corresponding racemate, which in turn appeared to be three times as active as morphine in preliminary experiments on human subjects. The drug inhibited cough following endotracheal i n t u b a t i ~ n ~ ~ and ' , produced satisfactory results at 0.5 mg doses, and excellent results with 1 mg doses, given orally 4-6 times per day to patients with various respiratory diseases32s. Additional clinical studies, especially with regard to the possible addictive properties of the drug, are required for a final evaluation. N-1', 1',3',3'- Tetramethylbutyl-Pdiethylaminoacetamide( TR-310)-It was first prepared by Malen and Boissier329 in a series of 25 substituted amides of basically substituted acetic acids. This series was prepared to prove that the aromatic nucleus of lignocaine (lidocaine, Xylocaine) may be replaced by suitably selected aliphatic radicals without loss of local anaesthetic activity. The compounds may be represented by the general formula ( X X X V I ) in which R1 and R2 represent RIRZN.(CH,), .CHR3.C O . N H R 4

(XXXVI) lower alkyl groups or together with N represent a nitrogen-containing heterocyclic radical, n stands for zero or one, R 3 for hydrogen or lower alkyl, and R4 represents a tertiary alkyl group. The compounds have local anaesthetic, analgetic, convulsant, spasmolytic, and pressor properties. The series was subsequently extended to include 26 additional compounds in

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which R4 is a tertiary aliphatic radical with up to 14 carbon atoms in a chain, or a cycloaliphatic group ; these compounds have local anaesthetic, analgetic, and antispasmodic a c t i v i t i e ~ I~n~ one . structure-activity it was found that the 1,1,3,3-tetramethylbutylgroup (CMe,.CH,.CMe,) in position R4 gave the highest values for local anaesthetic activity, which was further enhanced by the 2-methylpiperidino group in the position of RIRzN. I n a subsequent series of four papers332-335a detailed study of the pharmacological properties of most of the above compounds was made. Also included were a number of compounds in which R3 represents ethyl or propyl radicals or in which R4 represents straight-chain aliphatic radicals up to 12 carbon atoms, and a series of compounds in which the basic group was attached not to the acid moiety but to the amide nitrogen, e.g. of the formula RCO .NH .CH,. CH,. NEt,; R in this instance represents straightchain alkyl radicals up to 15 carbon atoms. All the above compounds have local anaesthetic and antispasmodic properties and some of them also have analgetic activity. The antitussive activity of the title compound ( X X X V I , R1 = R2 = Et, n = 0, R3 = H, R4 = CMe,.CH,.CMe,) was studiedz4 by means of KasC’sg7,de Vleeschhouwer’~~~~, and D ~ m e n j o z ’ methods s~~ and found to be slightly superior to that of codeine and about equal to that of carbetapentane. The drug was stated to have spasmolytic, local anaesthetic, and analgetic properties, and no depressant effects upon respiration. Its toxicity appeared to be low (LD,, mouse i.p. 260 mg/kg331),but it was stated to be convulsant in high doses. No clinical studies of the drug appear to have been published to date. Methaqualone-The compound (Metolquizolone, Melsedin, Tuazole, QZ-2, 2-methyl-3-o-tolyl-4-quinazolone, XXXVII, R = Me, R1 = o-tolyl, R2 = H) which may be regarded as a cyclic amide, was first synthesized as a potential analgesic by Kacker and Zaheer336in a series of compounds of the general

formula ( X X X V I I ) in which R represented hydrogen or lower alkyl, R1 phenyl or substituted aryl, and R2hydrogen. The synthesis followed a general method previously used to prepare similar compounds including a number ~ ~ ~hypnotic . activity of in which R2stood for chlorine in the 6 - p o ~ i t i o nThe some of the above compounds was discovered by Gujral, Saxena and T i ~ a r i who ~ ~ found ~ , the title compound superior to ethylphenylbarbituric acid. Some of the pharmacological actions of the drug were studied including its low acute toxicity (LD,, mouse, oral 1 g/kg, i.p. 200-300mg/kg; rat, oral 0.5 g/kg)339.A dose of 100 mg/kg given orally five times per week for six weeks was non-toxic to rats. The compound caused loss of righting reflex in mice a t doses of 90-100 mg/kg, inhibited the stimulant actions of 123

ANTITUSSIVE DRUGS

leptazole, picrotoxin, amphetamine, caffeine, or Meratran, and potentiated the depressant effects of Mebubarbital, methylpentynol, reserpine, or chlorpromazine. The central depressant effects of the drug were confirmed in a clinical which showed that 150 mg doses of the drug gave hypnotic effects which were superior in 54 out of 100 patients to those obtained with other hypnotics. Similar results were reported by Parsons and T h o m ~ o who n ~ ~found ~ that a dose of 150 mg of the drug was as effective as 200 mg cyclobarbitone. The antitussive effects of methaqualone were discovered by Boissier and P a g n ~ Tested ~ ~ ~ . in cats by Domenjoz’s method74, doses of 10 mg/kg i.v. inhibited cough completely for 25 minutes to 3 hours, while codeine had about the same effects in doses of 1-6 mg/kg i.v. No synergism between the drug and codeine was detected. I n guinea-pigs the drug had an ED,, of about 20 mg/kg i.p. against cough produced by an aerosol of N/2 sulphuric acid, while codeine was found to have the same effects at about 40 mg/kg i.p. Doses of 40 mg/kg i.p. of methaqualone caused no drowsiness in the animals. No depressant effects upon respiration, and no cardiovascular effects were found, and the drug was stated to possess slight spasmolytic activity. The authors recommended it for clinical trials as an antitussive drug. Kohli, Gupta and Bhargava141studied the antitussive action of the drug by Domenjoz’s method74 and found it to be ineffective a t doses of 1-2 mg/kg, but effective at 5 mg/kg. No clinical studies of the antitussive efficacy of the drug have appeared in print to date. Dextromethorphan (Romilar, d-3-methoxy-N-methylmor~hinan, XXXVIII)Dextromorphan may be regarded as being structurally derived from

IXXXVIII)

codeine (see formula I I ) , by elimination of the oxygen bridge C4-C5, the oxygen function on C6, and the double bond C7-C*. Its preparation was first described by Schnider and G r i i ~ s n e r ~ ~ ~ . I t may also be regarded as being the dextrorotatory methyl ether of raceniorphan, the narcotic and addictive properties of which are well known (c..f. reference 32). However, Isbell and Fraser181 showed that it was free from addiction liabilities while its laevorotatory enantiomer was highly addictive. In this series of compounds the d-enantiomers have no analgetic, sedative, or general morphine-like effectslsO.Derivatives of dextromethorphan, in which particularly the N-methyl and the 0-methyl groups had been replaced by other substituents, were recently stated to possess antitussive p r o p e r t i e ~ but ~ ~ ~no~ ~ pharmacological ~~, or clinical data on those latter compounds seem to have been published so far. 124

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The first thorough pharmacological study of dextromethorphan was carried out by Pellmont and B a ~ h t o l d Using ~ ~ ~ . four different methods for determining antitussive activity, they found the drug to be equal in potency to codeine in two of them54174,active a t 2 mg/kg i.v. in anothers5, and superior to codeine in a procedure using ammonia to induce cough. I t had practically no analgetic activity, no sedative action, and caused no inhibition of respiration ; no constipating or antidiuretic effects were noted. Reichle and F~-iebel'~ thought that the drug was representative of a new class of antitussives with little analgetic effects. Van DongenlG0found that doses of 2 mg/ kg S.C. inhibited cough for 6 hours, 4mg/kg S.C. for 8 hours, and that 5-10 mg/kg S.C. prevented cough in the cat when tested by the method of E r n ~ t Dextromethorphan ~~. is relatively more effective in humans than in rats or g u i n e a - p i g ~ l I~t~is. centrally active in doses of 0.25-2.0 mg/kg i.v., and it inhibits cough more than respiratione2. I t was reported to act more rapidly and more powerfully than codeine in guinea-pigs with cough induced by ammonia347,but it was found less active than codeine in the same species with cough elicited by acrolein132. Cough induced experimentally in healthy human subjects was apparently not influenced by dextromethorphan, as no significant differences were detected between 10 mg doses of dextromethorphan, 10 mg or 15 mg codeine, or p l a ~ e b o l ~ On ~ J ~the ~ . other hand, in a double blind study, it was found to be significantly better than placebo, with 10 mg doses being equal to 15 mg codeine144. Clinical studies of the use of dextromethorphan in the treatment of cough of various origins show that it is effective in doses which vary between 4 and 30 m9242934s-353. I t has been successfuIly used in infants and ~ h i l d r e n ~ " . ~ ~ ~ , in patients suffering from pulmonary t u b e r c ~ l o s i s ~ 5and ~ , ~as~ ~an, adjunct in surgical procedures associated with pulmonary diseases358. T o summarize, dextromethorphan appears to be a useful and effective antitussive drug, with an optimal dose of 10 mg given three to four times per day, and a maximal single dose of 30 mg. Doses of 10 mg seem to be about as effective as 15 mg of codeine. The incidence of side-effects is much lower than that encountered with codeine, and the drug has no sedative, analgetic, habit-forming, nor addictive properties. Normethadone (desmethylmethadone,HOE 10582, X X X I X , 6-dimethylamino-4,4diphenylhexan-3-one)-The compound differs from methadone by the absence of a methyl group attached to position 6. I t was synthesized by Bockmuhl and Ehrhardt359as one of a series of closely related compounds with analgetic activity in which numerous variations were made in the basic group, in branching of the chain, and in the nature of the group replacing carbon atoms 1 and 2. The structure of normethadone corresponds to the formula ( X X X I X ) and it is used as the antitussive principle in the German preparation Ticarda, which contains 7-5 mg normethadone hydrochloride and 10 mg Suprifen (1-(4-hydroxyphenyl)-2-methylaminopropanol) in tablets, or 1 per cent normethadone and 2 per cent Suprifen in liquid form.

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The early pharmacological and clinical results with the drug have been reviewed32. The drug has mainly analgetic and less important antitussive properties in guinea-pigss3gs7,and this was confirmed78in rats. Friebel and Reichle129found the drug to be relatively more potent as an antitussive in rats than in guinea-pigs or in humans. Van DongedGO, using Ernst’s method34 in cats, reported antitussive activity lasting for 6-7 hours with doses of 2 mg/kg S.C. which, however, inhibited ciliary movement. Doses of 5 mg/kg were stated to cause excitation. Using Domenjoz’s methodT4the drug was shown to have an ED,, of 0.3 mg/kg i.v., five times as active as codeine, and with a duration of effect of about 70 per cent of that of codeine141. In rats with cough produced by 0.02 per cent sulphur dioxide, a n ED,, of 14 mg/kg i.p. was found3s0,almost twice the potency of codeine. In clinical practice, r e p ~ r t s l indicate ~ ~ J ~ ~that the drug is inferior to some other antitussive drugs, but it is efficacious in cases of irritative Conflicting views exist on whether the drug is a d d i c t i ~ e ~ ~ > ~ ~ O . R-522-A molecular complex or possibly a salt of normethadone with 2,6-di-(-butyl)naphthalenedisulphonic acid, it was first described by Hengen and Ka~parek’~. They found it had about the same therapeutic index in rats as codeine, and a considerably better index than methadone. SchmidtlS9evaluated the compound in a clinical trial on 55 patients treated with 35-45 mg of the preparation per day for 4-6 weeks, and reported 30 good, 20 satisfactory, and 5 poor results. The compound was stated to have no influence upon blood pressure, haemogram, urine analysis, blood sugar levels in diabetics, or appetite, and no allergic manifestations, constipation, or development of tolerance were observed. l-Cyclopentyl-l-(,5’-N-morpholinoethyl) cyclopentane-2-one (Melipan, Ciba 10611, XL)-It may be regarded as somewhat related to normethadone ( X X X I X ) .

IXL I

N o details of the synthesis of the compound or its analogues, nor of its pharmacological properties, have been found in the literature to date. The only published report concerns a for antitussive activity in 28 volunteers who coughed regularly when exposed to a citric acid aerosol109 and in whom cough reflex was suppressed by 30 mg ofcodeine. I n a blind test using 25 and 50mg doses of the drug and 30mg of codeine, careful statistical evaluation showed that the drug was almost as effective as codeine, and that its antitussive activity was not increased when the dose was raised from 25 mg to 50 mg. Phenothiazine derivatives Dimethoxanate-Synthesized by von S ~ m a n dimethoxnnate ~ ~ ~ , (Cothera, 2‘-dimethylaminoethoxyethylphenothiazine- 10-carboxylate, XLI, R = H, 126

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R' = R2 = Me) was one of a series of compounds in which the phenothiazine nucleus remained unsubstituted (R = H), while R1 and R 2 were varied to include ethyl and isopropyl radicals. Chappel, Stegen and Grant142studied the pharmacological properties of these compounds and found them to be powerful antitussives when tested by Domenjoz's meth0d7~,with the antitussive activity increasing as the size of R1 and R2 increased. The dimethyl compound was found to be slightly less active than codeine, and the compound with R1 = R2 ==Pri twice as active as codeine. However, oral toxicity, antispasmodic activity, local anaesthetic action, and inhibition of gastric emptying rate increased also

(XLII as the size of R1and R2 increased, and for those reasons the title compound (R1 = R2 = Me) was chosen for further detailed study. I t was found to have neither anticholinergic nor antihistaminic activity, and it had no effect upon gastric secretion in the Shay rat. The drug had no influence upon spontaneous activity of the rat, and did not potentiate the hypnotic action of pentobarbital in the mouse. Doses of 2 mg/kg i.v. had no influence upon blood pressure or respiratory rate in the dog, and higher doses up to 8 mg/kg produced only a transient fall in blood pressure accompanied by slight tachycardia and tachypnoea, all of which returned to normal within 5-15 minutes. The compound in doses of 25 mg/kg S.C. had no analgetic effects in the mouse. The acute oral toxicity was found to be about the same as that of codeine in the mouse, but only 40 per cent that of codeine in the rat. Chronic toxicity tests in rats receiving 0.1, 0.06, and 0.04 per cent of the drug in their diet over a period of 32 weeks, equivalent to daily intakes of the drug of 45-75, 25-40, and 15-30 mg/kg respectively, showed normal growth curves in animals of both sexes. Dogs given daily oral doses of 50 mg/kg for one year gained weight and remained in good health. Chen, Biller and Montgomeryg1 compared the drug for duration of antitussive effects with codeine and a number of other antitussives. Challenging dogs with sulphuric acid aerosolg6 and administering the drugs orally either in doses of 1 mg/kg, or in therapeutically equivalent doses (e.g. 0.8 mg/kg dimethoxanate equivalent to 0.5 mg/kg codeine or to 0.2 mg/kg hydrocodone), they found dimethoxanate in both series of experiments superior to all other drugs except chlophedianol: dimethoxanate reduced cough by 75 per cent for about 3.5 hours, chlophedianol for 7-9 hours, and codeine for about one half-hour, while benzonatate, dextromethorphan, and noscapine failed to reach the level of 75 per cent inhibition of cough with the doses employed. Boissier and used both guinea-pigs challenged with N/2

127

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sulphuric acid aerosols3 and cats7* in their evaluations of the antitussive activities of a number of phenothiazine derivatives, mainly of the antihistamine or tranquillizer type, but also including dimethoxanate. They found the drug to be somewhat more active than codeine in the guinea-pig, and slightly less potent than codeine in the cat. The authors concluded that neuroleptic agents possess non-specific antitussive activities, not related to antihistaminic activity and not connected with the presence of the phenothiazine nucleus in the molecule of the drug. Clinical studies with dimethoxanate were carried out by Klein3G5, who evaluated the drug as a routine antitussive medication in 50 patients, and in 15 particularly severe cases of chronic cough, with doses of about 18 mg twice per day. Reactions of the 15 patients in the second group were evaluated with particular care. The onset of action of the drug was found to be rapid, usually within 5-10 minutes, with an average duration of effect of four hours. Severity and frequency of cough were both reduced, with complete suppression of cough after a single dose in 12 cases. No influence of the drug upon the excretion of sputum was noted, and no incompatibility with a large number of other drugs. No side-effects were seen, and the drug seemed to have no cardiovascular effects. The drug was superior to placebo, and was rated superior to the previously used hydrocodone by 12 patients and equally effective by two others. Parish366 conducted a double-blind study of the drug compared with placebo in 139 patients, the majority of whom suffered from coryza or allergic rhinitis. Ninety-three of the 95 patients treated with the drug reported excellent relief following treatment with doses of 25 mg every four hours in adult cases, and 8-18 mg for children. Of 44 cases treated with placebo, 41 reported slight transient relief, possibly due to the demulcent action of the preparation, and 3 obtained excellent relief. Thirteen cases of side-effects were seen in the series, usually slight drowsiness or nausea, but one patient known to be drug-sensitive developed an allergic reaction which cleared after cessation of medication. the series of phenothiazine Following the initial work cited derivatives was extended by Myers and Davis367to include compounds of the general structure ( X U ) with R = H in which the ether linkage in the side chain had been replaced by a thioether CH, . CH, .S .CH, .CH, .NR1R2, with R1 and R 2 representing Me, Et, or Pri. Further extensions of the series were carried out by who prepared a group of compounds of structure ( X L I ) in which R1 and R 2 were varied or in which NR1R2 represented a nitrogen-containing heterocycle, a second group in which both the length of the side chain and the nature of the basic group were varied, a third group containing variations in the nature of the ester linkage, and a fourth group in which R represented a variety of substituents in the 2- or 3-positions of the phenothiazine nucleus, with the ester linkage and the nature of the side chain as in formula ( X U ) but with variations in the basic group. Some forty compounds were prepared in this manner, and most of them were found to possess important antitussive activities in laboratory animals369. Derivatives of azaphenothiaziize Pipazethate-Variously named as Selvigon, D-254,2'- (2-piperidinoethoxy) ethyl 1-azaphenothiazine- 10-carboxylate; also (German nomenclature) 128

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4-azaphenothiazine- 10-carboxylate, or 10- thia- 1,9-diaza-anthracene9-carboxylate, or (Clzern. Abstr. nomenclature) 10H-pyrido[3,2b] [ 1,4]benzothiazine- 10-carboxylate ; this compound corresponds to formula ( X L I I ). The compound is closely related to dimethoxanate ( X U , R = H, R1= R2 -=Me), from which it differs in the nature of the nucleus and of the basic group in the side chain. The synthesis of pipazethate has so far not been reported? but a series of closely related basically substituted lower alkyl

esters of 1-aza- (or, according to German nomenclature, 4-aza-)phenothiazine- 10-carboxylic acid was prepared by Schuler and Klebe370and described as spasmolytics. The pharmacology of pipazethate was studied by Gulden371.The median lethal dose in the mouse was reported as 97 mg/kg i.p. and 214 mg/kg p.0.; the corresponding values in the rat were 70 and 560 mg/kg. The compound was reported to have hypnotic properties in mice with an ED,, of 106 mg/lcg. No cataleptic, anti-allergic? antihistaminic, or antiserotonin properties were observed. As a spasmolytic, the compound was found to have 5 per cent of the activity of atropine against acetylcholine, and to be 1.6 times as active as papaverine against barium-chloride-induced spasm. Its local anaesthetic activity was reported to be 40 per cent that of lignocaine. The drug was stated to be a n effective antitussive both by S.C. or oral routes, but neither the experimental method used nor the results obtained were given. Liba1372,on the other hand, reported that the drug had only slight local anaesthetic activity? and that no sedative effects could be observed in mice. The pharmacology of pipazethate as an antitussive in human subjects was first studied by H a ~ l r e i t e r The ~ ~ ~method . of Tiffeneau112was first applied to 35 healthy subjects and 160 patients; the authors found that the former group did not react to the challenging agent (acetylcholine). Of the 160 patients with chronic inflammatory conditions of the respiratory tract, 70 reacted by cough after challenge with an aerosol of 0.1 per cent acetylcholine, 49 reacted to 0.25 per cent, 5 to 0.5 per cent, and 7 to 1.0 per cent concentration. Bronchospasms occurred in a number of patients, but they were readily controlled by inhalations of hexamethonium aerosol. Jn a subsequent double-blind experiment? 120 patients were challenged with aerosols of the same range of concentration of acetylcholine as above, 30 minutes after receiving either 30 mg of codeine, 20 mg of pipazethate, or placebo. Cough was completely inhibited in 6 per cent of the patients treated with placebo, in 53 per cent of those treated with codeine, and in 41 per cent of' those given pipazethate. Inhibition of cough was particularly marked in cases of chronic bronchitis, while the drugs seemed to be ineffective in cases 129

ANTITUSSIVE DRUGS

of thoracoplasty, lobectomy, or silicosis. Prime374,using a similar technique, confirmed that it was not applicable to healthy volunteers who were nonsmokers. When repeating the test in another group of volunteers who were moderate smokers and admitted to having occasional slight cough, all of the subjects coughed after the challenge. A double-blind trial was then carried out with the latter group of 12 subjects, using doses of 20 mg pipazethate, 16 mg of codeine phosphate, or placebo, all of them given 20 minutes before challenge with acetylcholine aerosol. Cough rates before and after medication were determined individually and submitted to an analysis of covariance. The adjusted mean cough rates following administration of pipazethate, codeine, or placebo were found to be respectively 4.6, 7.9 and 14-0, with no variation in the cough rate before and after taking placebo. The author concluded that pipazethate was a potent antitussive drug. He stated furthermore, that oral doses of 20-40 mg appeared to be sufficient for most purposes; that the drug may be given in doses up to 160 mg per 24 hours without sideeffects; and that it appeared to be useful in endoscopic or bronchospirometric procedures. In clinical trials, pipazethate appears to be about as good as codeine in suppressing cough in patients suffering from pulmonary t u b e r c u l ~ s i s ~ ~ ~ * ~ ~ ~ and various respiratory disorders373. Side-effects were negligible or nonexistent and no signs of habituation or addiction were observed. I n summing up the above pharmacological and clinical evidence, pipazethate appears to be a useful antitussive drug, somewhat less potent than codeine, and with an unusually low incidence of side-effects. Obviously further clinical studies are needed for a more complete evaluation of the drug. Oxolamine-This compound (Perebron, 3-phenyl-5-(2-diethylaminoethyl)1,2,4-oxadiazole, XLIII, X = H, n = 2, R = NEt,) was first described by Silvestrini and Pozzatti117 in a series of six substituted oxadiazoles of the general formula (XLIII) in which X represented hydrogen or chlorine, n was varied from 1 to 3, and R represented dimethylamino, diethylamino, pyrrolidina,, or piperidino groups.

The pharmacology of the above compounds was studied by the same authors117,who reported that the acute i.p. toxicity was generally low. Some of the compounds showed local anaesthetic activity considerably greater than that of procaine, while others were much less potent. Only one had marked antispasmodic activity, being about twice as active as papaverine, while the others were as active as or less active than papaverine. Most of the compounds caused no significant cardiovascular effects in the cat in doses of 5 mg/kg i.v., while higher doses produced transient hypotension. Some evidence of respiratory stimulation was reported. The compounds were 130

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found to be inactive as analgesics in rats in the hot plate375 and in the p h e n y l q ~ i n o n etests, ~ ~ ~ but three of them were found to have analgetic activities similar to or greater than that of acetylsalicylic acid when tested ~ ~ ~of. the compounds showed an by the method of Randall and S e l i t t ~ One anti-inflammatory comparable to that of phenylbutazone, the others were less active. When tested for antitussive activity by the method of D ~ m e n j o z ~ all~ compounds , were found to be less active than codeine; however, in the acrolein aerosol test on g u i n e a - p i g ~ l ~ two ~ , compounds were found to be considerably superior, and one about equal to codeine. No discernible relationship between structure and biological activities of compounds of this series was detected; however, all those compounds which had antitussive activity also had analgetic activity on inflamed tissue. The title compound showed the most interesting profile in the above tests: low toxicity (LD,, 208 mg/kg mouse, i.p.), weak local anaesthetic activity, and a high degree of antitussive action, were combined with good anti-inflammatory and good analgetic activities upon inflamed tissue. S i l v e ~ t r i n i ~ ~ ~ studied the compound in detail and found it to be twice as potent as codeine in guinea-pigs by means of the ammonia vapour tests4, but it showed only about one-third to one-fifth of the activity of codeine when tested by Domenjoz's method74. The drug did not inhibit nervous conduction, was found to be inactive at the neuromuscular junction, and did not potentiate the hypnotic action of barbiturates. The anti-inflammatory activity of oxolamine was compared with that of phenylbutazone and of acetylsalicylic and equipotent doses were reported to be 50, 20 and 100 mg/kg rat, s.c., respectively. The drug was also found to have anti-inflammatory action in the rat oedema test3s0, in which phenylbutazone and acetylsalicylic acid were both found to be inactive. O n the other hand, it did not retard the development of connective tissue following the subcutaneous implantation of a cotton pellet3s1. Its lack of analgetic activity in the hot plate375and the p h e n y l q ~ i n o n etests ~ ~ ~was confirmed117. The marked analgetic activity of oxolaiiiine upon inflamed tissue377 was found to be equal to that of phenylbutazone or of acetylsalicylic acid, but inferior to that of codeine or of morphine. The antipyretic activity of the drug was reported to be equal to that of phenylbutazone and about one-half that of acetylsalicylic acid. As a spasmolytic, oxolamine was stated to be about as active as papaverine, and its local anaesthetic activity equalled that of procaine. The drug had no cardiovascular effects in doses of 20 mg/kg rat i.p. ; higher doses caused transient hypotension. Oxolaniine did not inhibit intestinal peristalsis, and had no effects upon diuresis, conditioned reflexes, or monoamine oxidase activity; neither did it have any influence upon convulsions induced by electroshock, leptazole (pentylenetetrazol) , or strychnine. Toxicity was relatively low. The author concluded that the mode of action of oxolamine was different from that of morphine or codeine. The possibility of explaining the antitussive action of oxolamine as a synergism between its peripheral anti-inflammatory and decongestant activities and its central effects was also discussed : as the peripheral stimuli originating in the respiratory tract are diminished, the centralIy mediated effects of the drug may be relatively increased. An additional pharmacological study of oxolamine is in 131

Ah-‘lTTUSSTVE DRUGS

Clinical investigations of the drug were carried out using the doubleblind method with a positive (codeine) and a negative (placebo) control. Oxolamine was given as the citrate salt, usually in a syrup, in doses of 100 mg salt (=56 rng base) 4-5 times per day, and codeine was administered in the same manner in 30 mg doses, equivalent to 22 mg base. A high proportion of patients with tracheobronchitis were improved by ~ x o l a m i n e and ~ * ~almost one-half of a group of elderly hospitalized patients improved384.Oxolamine also benefited nearly a half of patients with pulmonary tuberculosis385. Controlled cIinica1 investigations in patients suffering from chronic respiratory conditions, in both a d ~ l t s 3 8and ~ children3s7, and in bronchitis cases388 gave moderately good results. A re-appraisal of these results showed that 100 mg of oxolarnine citrate was equivalent to 30 mg codeine ph0sphate~8~. Summarizing the above results, oxolamine appears to be a potentially useful drug, characterized by low toxicity, antitussive activity in man somewhat less than one-half of codeine, with analgetic activity in the range of that of acetylsalicylic acid, antipyretic activity about one-half that of the latter, and anti-inflammatory activity about 40 per cent that of phenylbutazone. The unique combination of these activities in one single compound may prove to be of value, but undoubtedly additional clinical studies are needed for a more complete evaluation of the drug. Piperazine derivatives-Compounds having the general structure ( X L I V ) in which R represented a mono- or polyhydroxylated alkyl group or an R3

R2

I

(XLI V ) alkoxyalkyl group, with R1and R2representing hydrogen or hydroxyl, and R3 hydrogen or methyl, were synthesized by Morren3”-3”. The compounds were stated to have antitussive properties, and one of them (XLIV, R = CH,.CH,.OH, R1= R2= OH, Ii3 = H) was claimed to have 150 per

cent of the activity of codeine. Morren246also prepared a compound of the structure ( XLV) which was claimed to have antitussive activity. 132

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Piperidine derivatives-Compounds o f the general formula ( X L V I ) were also claimed to have antitussive properties. Stern and Watt394described compounds with X = Ph, Y = OH or 0-acyl, R = (CH2),,K1 in which n = 2-6 and R1represented an alkoxy, aryloxy, aralkoxy, or cycloalkoxy group. The compounds were stated to have analgetic and cough centre depressant activities. Another series of c0mpounds~9~ in which X represented

x (XLVI)

the 2'-propyne-l'-yl group, CH,. C=CH, Y was a propionyloxy group, OCOEt, and R a phenethyl group, was stated to have antitussive, analgetic, and local anaesthetic activities. No pharmacological or clinical studies of the piperazine or piperidine derivatives mentioned above have been published to date. 1-Hydroxycyclopentanecarboxylic acid derivatives-A study of over a hundred derivatives of this acid and o f 1-aminocyclopentanecarboxylic acid showed that some of these compounds possessed antitussive activity equal to one half that of codeine when tested in the cat against chemical irritation65a. The compounds tested included those with one or two tertiary amino or quaternary ammonium groups. I n contrast to the findings of some workers, Ellis, Golberg, King and Sheard65afound that activity present in a tertiary amine was usually retained on quaternizing this group. Other Pharmacologically Active Agents Investigatedf o r Use in Cough Therapy Some sympathomimetics (isoprenaline, isoproterenol)39G-400,metham~hetamine~Ol-~O~, have been used successfully, mostly in combined preparations. A few smooth muscle spasmolytics (atropine120J32, adiphenine70y132,407, p a p a ~ e r i n e ~ ~have p ~ ~ ~low ) activity. prometha~ine~~~~364~40~~~10, Certain antihistamines (mepyramine132,3G4~40*, T h i a z i n a m i ~ m ~a~n~t9a ~ o l i n e ~ ltri~elennamine~O9~~~, ~~~l~, trimepra~ine~'*~~~* 418,419, tripr0lidine~~~3~~0) are only weakly active, but others (diphenhydramine104-106,411-413, c h l o r ~ y ~ l i ~ i nare e ~ ~clinically ~ ~ ~ ~ ~ effective. ~ ~ ~ ~ ) Some tranquillizers t h i o r i d a ~ i n e ~ reserpine141, ~~l~~~, 439-432) have weak antitussive activity, but others (azacyclonol, benactyzine, rnepr0bamatel30J~~)are ineffective. The ganglion blocking agents hexam e t h ~ n i u r nand ~~ pentameth~nium~ are ~ . effective ~~~ only against experimental cough induced by lobeline. Certain local anaesthetics (lignocaine, procaine70) are weak antitussives, but amethocaine (tetracaine) is highly a c t i v P . Amongst the hypnotics and sedatives, p e n t o b a r b i t ~ n e l land ~~~~~ phenobarbitone3G0 are inactive, but thiopentone has some antitussive activity62. RETROSPECT AND PROSPECTS

When considering the progress in a given field it is almost inevitable that a number of strong impressions will be gained. This has been particularly

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true for this review of the medicinal chemistry of antitussives. Judging by the number of new antitussive compounds which have been synthesized, studied pharmacologically, and in many cases introduced into clinical use, there would appear to have been much progress in the field. Indeed, in many respects this is certainly the case: quite a number of the new compounds are effective antitussives, free from addictive liability and most of the side-effects associated with the older opium alkaloids. However, codeine remains the most widely utilized drug for antitussive therapy, and only one of the newer drugs, dextromethorphan, exceeds codeine in potency in terms of the clinical dose. I t would seem that we are still far from having an ideal antitussive drug. I n so far as the chemistry of existing antitussive drugs is concerned, the common characteristic of the opium alkaloids and their close derivatives with antitussive activity, as well as of the synthetic antitussive drugs, is the presence of a tertiary amino group. The nitrogen atom of this group may be contained in an open chain or in a cyclic structure, and little, if any, difference in antitussive activity seems to result fiom this variation. The morphine alkaloids and their close derivatives seem to belong to a particular class of compounds with antitussive action, with the basic nitrogen atom contained in a ring system of very special character. The analgetic activities of most of these compounds may account for a large part of their antitussive activity, with the exception of dextromethorphan, in which analgetic activity is largely absent. However, it has been said that the antitussive action of codeine may be due to the subjective ‘sense of wellbeing’ which it seems to impart to the patients. The synthetic antitussives, most of which have been prepared in order to obtain compounds free from the noxious side-effects of the morphine alkaloids, including the danger of addiction, seem to have one feature in common. O n one end of the molecule we find usually an accumulation of large bulky groups, such as aryl, aralkyl, cycloalkyl, or heterocyclic groups. These groups might possibly perform a shielding action after the molecule has become attached to the receptor site. The basic nitrogen is usually found near the other end of the molecule. The linkages between the ‘bulky end of the molecule’ and the basic nitrogen may be effected by various means, but two main types of structures appear to be closely discernible: first, those with a superficial resemblance to antispasmodic drugs, and second, compounds with an equally superficial resemblance to synthetic analgesics related to methadone. An example from the first group of compounds may, perhaps, show the relationship. The dialkylaminoalkyl esters of phenothiazine-10-carboxylic acid were found to have important antispasmodic activity of a neurotropic, atropine-like c h a r a ~ t e r ~The ~ ~ ?same ~ ~ ~compounds . were also synthesized independently and a t about the same time by von Seemanri and Grant, who subjected them later on to a number of structural modifications. They noted, inter alia, that anticholinergic activity was reduced by insertion of one or more carbon atoms between the nitrogen of the phenothiazine ring and the carboxylic acid group, and was not influenced by substitution in the phenothiazine nucleus436.This observation seemed to confirm Pfeiffer’~~~’ earlier thoughts about the structural requirements for anticholinergic activity.

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Pfeiffer had theorized that certain substances with anticholinergic activity had structures in which the interatomic distances between the centres of each one of the two oxygen atoms in, for example, an ester group and the centre of the methyl group on the nitrogen resembled closely those found in acetylcholine itself. This should theoretically enable such compounds to become attached to the same receptor sites as acetylcholine. Calculations of the bond distances gave values of 5.3 A and 7.0 A for acetylcholine, and a number of acetylcholine antagonists showed indeed approximately the same values for the distances between each one of the two oxygen atoms and the methyl group on the nitrogen. Pfeiffer's theory being perfectly applicable to the above dialkylaminoalkyl esters of phenothiazine- 10-carboxylic acid, von Seemann speculated that a radical change in the structure might conceivably reduce anticholinergic action. The results vindicated this speculation : lengthening of the side chain by one ethoxy group gave basically substituted alkoxyalkyl esters such as, e.g. dimethoxanate, in which anticholinergic action had virtually disappeared, while direct smooth muscle relaxant activity was greatly enhanced. Moreover, those compounds were distinguished by pronounced antitussive activity, which was later found to be totally absent in the corresponding dialkylaminoalkyl esters438. Parallel differences in the nature of biological activities were also found between the basically substituted alkyl esters and the corresponding alkoxyalkyl esters of I-azaphenothiazine- 10-carboxylic a ~ i d ~ ~ 0 - ~ 7 ~ . Another example in this class of compounds may be equally illustrative. Adiphenine is known to possess very weak antitussive properties, while the closely related caramiphen has moderate antitussive activity, conceivably brought about by the comparatively simple change in the nature of one of the two phenyl groups of adiphenine. Lengthening of the side chain of caramiphen gave carbetapentane, which possesses very marked antitussive activity. I n this series, too, the increase in antitussive activity obtained by lengthening of the side chain seemed to be accompanied by a decrease in anticholinergic effect. Incorporation of an ethoxy group into a basically substituted alkyl side chain to obtain enhanced antitussive activity was also successful in the case of oxeladin. At this juncture it should also be remembered that the basically substituted alkoxyalkyl side chain often imparts antitussive activity14, and that dodecyl polyethylene oxide ether inhibited pulmonary stretch receptor^^^^^^^^. It would appear that the ether linkage in the side chain of antitussive drugs performs a very useful function. I n contrast to the above group of compounds, in which the basic group is attached to the bulky or shielding part of the molecule through a side chain carrying a n ester linkage, the second group of compounds does not possess such an ester group. The compounds in this class have a superficial resemblance to methadone : they are characterized by the presence of a quaternary carbon atom which carries a t least one and usually two bulky substituents, and to which the alkylene side chain carrying the basic nitrogen atom is attached directly. The fourth valency on the quaternary carbon atom may be occupied by a polar radical, such as a nitrile group as in isoaminile or a hydroxyl group as in IV

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Hoe 10682, or in KAT-256; or one of the alkyl groups attached to the basic nitrogen atom might be linked back to the quaternary carbon atom as, e.g. in pipendyl methane. A number of other variants in the nature of this group have been tried, with some measure of success, and its character would seem to be not too critical. The linkage between the basic nitrogen atom at one end of the molecule, and the bulky substituent at the other, is apparently not limited to an alkylene chain. In compounds such as methaqualone or oxolamine the link appears to be effected by a -C(R)=Ngroup. I t is not surprising, especially in view of the complex nature of cough, that certain compounds with antitussive properties do not belong to the two classes mentioned above: benzonatate, sodium dibunate, and TR-310 are among the most notable exceptions. Furthermore, it has been shown on a number of occasions that quaternization oi' a tertiary amino group reduced or destroyed antitussive activity : nevertheless, certain quaternary salts have been shown to be effective antitussives"", and somc of them have even found clinical acceptance (Monadyl, Lysobex). On the basis of the foregoing summary it would seem that the field of synthetic antitussive drugs is capable of wide expansion in the future, not too much limited by theoretical considerations : numerous varieties of compounds with spasmolytic actions of a musculotropic character, or with analgetic activities of the morphine type, might conceivably be transformed by comparatively simple modifications into useful antitussive drugs. We should, however, like to sound a note ofwarning a t this point: it seems rather pointless to increase the number of antitussive drugs available to the physician in the absence of a reasonable expectation that such new drugs would be more effective than codeine. I n clinical practice very few of the drugs discussed in this review have proved to be successful in doses smaller than equally effective doses of codeine. Although a number of the new drugs do not show the objectionable side-effects of codeine, detailed clinical studies have brought to light a number of other side-effects which might become statistically more important as those drugs gain wider acceptance. I t is our belief that any new antitussive drugs synthesized according to the modes outlined above may ultimately suffer from similar disadvantages. There seems to be no doubt that the physiological and pathological phenomena involved in the problem of cough will have to be made the subject of truly fundamental studies before any major progress may be expected. Only after a thorough elucidation of those phenomena will it be possible for the pharmacologist to develop investigative methods by which the influence of drugs upon the reflexogenic areas, upon afferent and efferent pathways, and above all upon the central regulatory mechanisms, may be measured specifically and with some degree of accuracy. And only after such methods have become established will it be possible to guide the chemist towards the synthesis of antitussive drugs with specific and well-defined activities. REFERENCES

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GIULIANO and ROSA Minerva nied., Torino 1955, 46/II, 1502 Praxis 1956, 45, 56 NAEGELI TOJAMinerva med., Torino 1956, 47, 1998 CAVALCA, Gazz. int. med. chir. 1956, 61, 1653 212. BASABE, GENTILE and CROCIONI Sem. med., B. Aires 1957. 110, 766 213. KAUCHTSCHISCHWILI G a z z . med. ital. 1957, 116, I49 2 14. JULIANI and PAGNOTTA G. Clin. rned. 1957, 38, 589 215. FIORArch. ital. Otol. 1957, 68, 1011 216. BALDINI Gazz. med. ital. 1958, 117, 152 217. WILSON, FARBER and MANDEL Antibiot. Med. 1958, 5, 567 218. VALENTI and UE PALMA Gazz. mrd. ital. 1958, 117, 194 219. HANKE Praxis 1958, 47, 610 220. VERGANI, PAGANI and LUPACCHINI Gazz. med, ital. 1956, 115, 200 221. HUSEN Tuberk Arzt 1958, 12, 248 222. NEUMANN Rev. mid. Suisse rorn. 1956, 76, 738 223. MASIRiv. Clin. pediat. 1957, 59, 87 224. CARUGHI Prensa. mid. argent. 1957, 44, 3621 225. GOTTIand GEROCARNI Clin. pediat., Bologna 1957, 39, 831 226. KOIKYWien. med. Wschr. 1958, 108, 493 227. FRANCESCHETTI G a z z . med. ital. 1958, 117, 213 228. ALEm and PALATRESI Gazz. int. med. Chir. 1956, 61, 1660 229. CATTANEO Minerva anest., Torino 1959, 25, 373 230. SURIANI Oto-rino-laring. ital. 1958, 26, 377 Pract. oto-rhino-laryng. 1957, 19, 339 23 1. UIAMANT 232. SIMON Ann. Allergy 1957, 15, 521 J . Amer. geriat. Soc. 1960, 8, 107 233. SIMON 234. f h o N (Council Report) J . Amer. med. Ass. 1959. 170, 1927 235. Swiss Patent 234,452 (1945) ; Chem. Abstr. 1949, 43, 6229 236. Swiss Patent 246,199 (1947) ; Chem. Abstr. 1949, 43, 6229 237. Swiss Patents 249,036-249,043 (1948); Chem. Abstr. 1949, 43, 6229 238. Swiss Patent 272,708 (1951); Chem. Abstr. 1952, 46, 4563 239. ROTHSem. H@, Paris 1956, 32, 325 240. LIECHTISchweiz. med. Wschr. 1950, 80, 484 GAENSLER and 13ADGER DG. Chest 1954,25,532 24 1. ABELMANN, 242. CASSand FREDERIK J . Lab. clin. Med. 1956, 48, 879 243. HUDSON Lancet 1952, I, 1310 244. SNYDER Laryngoscope, St. Louis 1953, 63, 1008 245. SEGAL,DULFANO and HERSCHFUS Transactions OJ' the 48th Annual Meeting o f the National Tuberculosis Assn., Boston 1952, p. 374 246. Belg. Patent 520,988 (1953); Chem. Abstr. 1959, 53, 8174; Brit. Patent 753,779 (1956); Chem. Abstr. 1957, 51, 7443 Brux.-me'd. 1954, 34, 422 247. DEPOORTER 248. PARISHMed. Times, N.Y. 1955, 83, 870 249. SIRONIMineroa anest., Torino 1956, 22, 413 250. BARRANCO and COTTONE Acta anaesth., Padova 1958, 9, 171 251. TARTARO G a z z . med. ital. 1959, 11, 36 252. CARTERand MALEYAmer. J . med. Sci. 1957, 233, 77 253. HALPERN Arch. int. Pharmacorlyn. 1938, 59, 149 Arzneimitt. Forsch. 1957, 11, I, 217 254. ENGELHARDT 255. HOOKTher. d. Gegenw. 1957, 96, 384 Bull. Soc. chim. Fr. 1959, 1895 256. NAJER,GIUDICELLI and CHABKIER 257. U S . Patent 2,963,485 (1960); Chem. Abstr. 1961, 55, 14484 258. NAJER,CHABRIER and GIUDICELLI Bull. Sac. chim. Fr. 1958, 355 259. CHEYMOL, GIUDICELLI, CHABRIER and NAjERArch. int. Pharmacodyn. 1960,125, 12 1

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ANTITUSSIVE DRUGS

260. U.S. Patent 2,952,685 (1960) ; Chem. Abstr. 1961, 55, 11441 Farmakol. i. Toksikol. 1957, 20, 6, 56 261. POLEZHAEVA 262. PETROW, STEPHENSON and WILDJ . Pharm., Lond. 1958, 10,40 263. DAVID,LEITH-ROSS and VALLANCE J . Pharm., Lond. 1957, 9, 446 Practitioner 1957, 178, 353 264. ROBERTS 265. British Patent 765,510 (1957); Chem. Abstr. 1957, 51, 14810 266. German Patent 960,462 (1957); Chem. Abstr. 1959, 53, 16077 267. German Patent 964,499 (1957) ; Chem. Abstr. 1959, 53, 16077 268. German Patent 964,500 (1957) ; Chem. Abstr. 1959, 53, 17060 269. U.S. Patent 2,854,472 (1958); Chem. Abstr. 1959, 53, 11317 270. MOFFETT and ASPERGREN J. Amer. chem. Soc. 1957, 79,4451 JONES,HOPPE and BECKER J . Pharmacol. 1949, 96, 1 271. LANDS,ANANENKO, 272. KRAUSE Arzneimitt. Forsch. 1958, 8, 553 273. CHAPPEL, STEGEN and RoNA-Personal communication 274. BOISSIER and PAGNYThkrapie 1960, 15, 93 275. CHRISTOFFEL and KOLBERG Med. Klinik. 1958, 53, 1507 276. ZEHBEMedizinische 1958, No. 36, 1401 277. BRENNER-GODDERZ Med. Klin. 1959, 54,2004 Munch. med. Wschr. 1959, 101, 676 278. EIDMANN 279. SCHMIEDEL Ther. d. Gegenw. 1959, 98, 239 280. SCHUMACHER Ther. d. Gegenw. 1959, 98, 581 281. FESERHippokrates, Stuttgart 1960, 31, 28 282. PETERSEN Dtsch. rned. J . 1960, 11, 235 283. JANSSEN, JAGENEAU and HUYGENS J . med. pharm. Chem. 1959, 1, 299 and SHANECanad. med. Ass. J . 1960, 83, 1093 284. MORRIS 285. German Patent 1,051, 281 (1959); Chern. Abstr. 1960, 54, 24556; British Patent 811,659 (1959); Chem. Abstr. 1960, 54, 424 286. British Patent 815,217 (1959); Chem. Abstr. 1960, 54, 1453 Atzneinzitt. Foisch. 1958, 8, 550 287. G~SSWALD 288. ZURLINDENMedizinische 1958, 22, 959 289. BOYDand BOYDCanad. rned. Ass. J . 1960, 83, 1298 290. DRAFTher. d. Gegenw. 1958, 97, 477 291. LORDICK and POPPELMA"Med. Klin. 1958,53,2157 292. PALMDtsch. med. J . 1959, 10, 64 Minerua rned., Totino 1959, 50, 4396 293. TACCANI 294. SISCHKA Wien. med. Wschr. 1959, 109, 926 295. KLEYDtsch. med. J . 1959, 10, 580 296. KUKOWSKI Ther. d. Gegenw. 1960, 99, 36 Dtsch. med. J . 1960, 11, 95 297. PRUSSING 298. SCHROER H.N.O. (Berl.) 1960,8, 183 299. U.S. Patent 2,827,460 (1958); Chem. Abstr. 1959, 53, 415 and STEIN Arzneirnitt. Forsch. 1959, 9, 94 300. LINDNER 301. BRANDSCHWEDE Med. Klin. 1959, 54, 2185 Medizinische 1959, 1878 302. DANNENBERG 303. Belgian Patent 588,825 (1960) and French Patent M-160 (1960) 304. ENGELHORN Aizneimitt. Forsch. 1960, 10, 785 Arzneimitt. Forsch. 1960, 10, 794 305. RIEBEL 306. ADAMSON J . chem. SOG.1950, 885 and GREENNature, Lond. 1950, 165, 122 307. ADAMSON 308. GREENBrit. J . Pharmacol. 1953, 8, 2 309. KIMURA, YABUUCHI and TAMURA Pharm. Bull., Tokyo 1958, 6, 159 and FRASER J . Pharmacol. 1953, 109, 417 310. ISBELL 31 1. ANON.United Nations Documents E/NS., 1955, summaries 1 and 5, and E/NS., 1956, summaries I , 3 and 5

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312. KAsB, KAKU,YAMAMOTO, TANAKA, 'I'AKASAKI and NAGAOPharm. Bull., Tokyo 1955, 3, 394 313. KIMURA and YABUUCHI Chem. pharm. Bull., Tokyo 1959, 7, 171 314. KIMURA, OCAWAand YABLJUCHI Chem. Pharm. Bull., Tokyo 1959, 7, 175 315. U.S. Patent 2,739,968 (1956); Chem. Abstr. 1960, 54, 15596 316. NAIRand HAARN.Y. St. J . Med. 1956, 56, 1773 3 17. KAsB,YUIZONO, YAMASAKI, YAMADA, 10,TAMIYA and RONDO Cliem. Pharm. Bull., Tokyo 1959, 7, 372 318. SUGIMOTO, KOWA,HIGAKI, NAKAMURA and YASAKA Chem. Pharm. Bull., Tokyo 1960,8, 745 319. U s 6 and YUIZONO Chem. Pharm. Bull., Tokyo 1959, 7, 378 320. U.S. Patent 2,913,459 (1959); Chem. Abstr. 1960, 54, 3203 321. PLISNIER C.R. SOC.Biol., Paris 1958, 152, 1267 and VANDERSMISSEN Arch. int. Physiol. 1954, 62, 433 322. CHARLIER 323. GHIDINI G. Clin. rned. 1956, 37, 1666 324. FIORArch. ital. Otol. 1957, 68, 660 325. SCALAIS Scabel, Brux. 1959, 112, 220 J. Amer. chem. SOC.1956, 78, 3862 326. JANSSEN 327. D E L I G Nand ~ GILLES Ane'sth. Analg. 1957, 14, 51 328. SEREMBE and VISENTINI Gazz. med. ital. 1959, 118, 113 Bull. Soc. chim. Fr. 1956, 923 329. MALENand BOISSIER ., and BOISSIER Bull. SOC.chim. Fr. 1956, 926 330. M A U G ~MALEN 331. BOISSIER, MALENand DUMONT C.R. Acad. Sci., Paris 1956, 242, 1086 DUMONT and MALENThe'rapie 1956, 11, 745 332. BOISSIER, 333. BOISSIER, DUMONT and MALENAne'sth. Analg. 1956, 13, 569 334. BOISSIER, DUMONT, MALENand M A U GThe'rapie ~ 1957, 12, 223 335. BOISSIER, DUMONT and MALENThe'rapie 1957, 12, 551 and ZAHEER J . Indian chem. SOC.1951, 28, 344 336. KACKER 337. GRIMMEL, GUENTHER and MORGAN J . Amer. chem. SOC.1946, 68, 542 338. GUJRAL, SAXENA and TIWARI Indian J . med. Res. 1955, 43, 637 339. BOISSIER, DUMONT and MALENThbrapie 1958, 13, 30 340. RAVINAPr. mkd. 1959, 67, 891 and THOMSON Brit. med. J. 1961, Z, 17 1 34 1. PARSONS 342. BOISSIER and PAGNYMedicina Experimentalis, Base1 1959, 1, 368 343. U.S. Patent 2,676,177 (1954); Chem. Abstr. 1955, 49, 6325 344. British Patent 843,752 (1960); Chem. Abstr. 1961, 55, 4544 345. British Patent 837,512 (1960); Chem. Abstr. 1960, 54, 24817 346. PELLMONT and BACHTOLD Schweiz. med, Wsclir. 1954, 84, 1368 and MARCIJCCI Arch. ital. Otol. 1957, 68, 404 347. MARCATO 348. CASSand FREDERIK New Engl. J. Med. 1953, 249, 132 and ANDOSCA Amer. J . med. Sci. 1954, 227, 291 349. CASS,FREDERIK 350. MAURER Dtsch. med. Wsclir. 1955, 80, 351 351. TUNNERHOF and SCHWABE, Kliri. Wschr. 1955, 33, 576 352. KUMMER Praxis 1955,44, 132 Wien. med. Wschr. 1959. 109, 507 353. SKURSKY 354. HOTTINGER Schweiz. med. Wschr. 1954, 84, 1372 355. HUPERZ Medizinische 1958, 27-28, 1105 356. RALPHAmer. J. med. Sci. 1954, 227, 297 and DI PASQUALE Schweiz. 2. Tuberk. 1955, 12,80 357. CAPELLO 358. GRAFEMedizinische 1958, 43, 1741 and EHRHARDT Liebigs Ann. 1948,561,52 359. BOCKMUHL 360. WIEDEMEIJER, KRAMER and DE *JONGH Acta Pl@ol. Pharmacol. Need 1960, 9, 50 1 361. DE BEULEBelg. Tijdschr. Geneesk. 1952, 8, 220

143

ANTITUSSIVE DRUGS

362. 363. 364. 365. 366. 367. 368. 369. 370. 371. 372. 373. 374. 375. 376. 377. 378. 379. 380. 381. 382. 383. 384. 385. 386. 387. 388. 389. 390. 391. 392. 393. 394. 395. 396. 397. 398. 399. 400. 401. 402. 403. 404. 405. 406. 407. 408. 409. 410. 411. 412. 413. 414. 415.

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